Publications by authors named "David Cameron-Smith"

208 Publications

Plasma B Vitamers: Population Epidemiology and Parent-Child Concordance in Children and Adults.

Authors:
Stephanie Andraos Beatrix Jones Clare Wall Eric Thorstensen Martin Kussmann David Cameron-Smith Katherine Lange Susan Clifford Richard Saffery David Burgner Melissa Wake Justin O'Sullivan

Nutrients 2021 Mar 2;13(3). Epub 2021 Mar 2.

The Liggins Institute, The University of Auckland, Auckland 1023, New Zealand.

Scope: B vitamers are co-enzymes involved in key physiological processes including energy production, one-carbon, and macronutrient metabolism. Studies profiling B vitamers simultaneously in parent-child dyads are scarce. Profiling B vitamers in parent-child dyads enables an insightful determination of gene-environment contributions to their circulating concentrations. We aimed to characterise: (a) parent-child dyad concordance, (b) generation (children versus adults), (c) age (within the adult subgroup (age range 28-71 years)) and (d) sex differences in plasma B vitamer concentrations in the CheckPoint study of Australian children.

Methods And Results: 1166 children (11 ± 0.5 years, 51% female) and 1324 parents (44 ± 5.1 years, 87% female) took part in a biomedical assessment of a population-derived longitudinal cohort study: The Growing Up in Australia's Child Health CheckPoint. B vitamer levels were quantified by UHPLC/MS-MS. B vitamer levels were weakly concordant between parent-child pairs (10-31% of variability explained). All B vitamer concentrations exhibited generation-specificity, except for flavin mononucleotide (FMN). The levels of thiamine, pantothenic acid, and 4-pyridoxic acid were higher in male children, and those of pantothenic acid were higher in male adults compared to their female counterparts.

Conclusion: Family, age, and sex contribute to variations in the concentrations of plasma B vitamers in Australian children and adults.
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http://dx.doi.org/10.3390/nu13030821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001009PMC
March 2021

Comparing Response of Sheep and Cow Milk on Acute Digestive Comfort and Lactose Malabsorption: A Randomized Controlled Trial in Female Dairy Avoiders.

Authors:
Aahana Shrestha Linda M Samuelsson Pankaja Sharma Li Day David Cameron-Smith Amber M Milan

Front Nutr 2021 15;8:603816. Epub 2021 Feb 15.

The Liggins Institute, The University of Auckland, Auckland, New Zealand.

Sheep milk (SM) is a possible alternate dairy source for those who experience digestive symptoms with cow milk (CM). While both the milks contain lactose, one of the causes for self-reported intolerance to CM, the composition of SM and CM also differs across proteins and fats, which have been shown to impact digestive processes. To compare the acute digestive comfort and lactose malabsorption of SM to CM in female dairy avoiders. In a double-blinded, randomized cross over trial, 30 dairy-avoiding females (aged 20-30 years) drank 650 mL of SM or CM (each reconstituted from spray dried powder) following an overnight fast, on two separate occasions at least 1 week apart. Blood samples were collected for glucose and insulin assessment, and single nucleotide polymorphisms of the lactase () gene (C/T and G/A). Breath H and visual analog scale (VAS) digestive symptom scores were recorded at fasting and regular intervals over 4 h after ingestion. Eighty percentage of study participants were lactase non-persistent (LNP; CC and GG genotype). Digestive symptoms, including abdominal cramps, distension, rumbling, bloating, belching, diarrhea, flatulence, vomiting, and nausea, were similar in response to SM and CM ingestion (milk × time, > 0.05). Breath H was greater after CM than SM (72 ± 10 vs. 43 ± 6 ppm at 240 min, < 0.001), which may be due to greater lactose content in CM (33 vs. 25 g). Accordingly, when corrected for the lactose content breath H did not differ between the two milks. The response remained similar when analyzed in the LNP subset alone ( = 20). Despite a higher energy and nutrient content, SM did not increase adverse digestive symptoms after ingestion, relative to CM, although there was a reduced breath H response, which could be attributed to the lower lactose content in SM. The tolerability of SM should be explored in populations without lactose intolerance for whom underlying trigger for intolerance is unknown.
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http://dx.doi.org/10.3389/fnut.2021.603816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917135PMC
February 2021

Acute Nutritional Ketosis and Its Implications for Plasma Glucose and Glucoregulatory Peptides in Adults with Prediabetes: A Crossover Placebo-Controlled Randomized Trial.

Authors:
Sakina H Bharmal Jaelim Cho Gisselle C Alarcon Ramos Juyeon Ko David Cameron-Smith Maxim S Petrov

J Nutr 2021 Apr;151(4):921-929

School of Medicine, University of Auckland, Auckland, New Zealand.

Background: The potential of a ketone monoester (β-hydroxybutyrate; KEβHB) supplement to rapidly mimic a state of nutritional ketosis offers a new therapeutic possibility for diabetes prevention and management. While KEβHB supplementation has a glucose-lowering effect in adults with obesity, its impact on glucose control in other insulin-resistant states is unknown.

Objectives: The primary objective was to investigate the effect of KEβHB-supplemented drink on plasma glucose in adults with prediabetes. The secondary objective was to determine its impact on plasma glucoregulatory peptides.

Methods: This randomized controlled trial [called CETUS (Cross-over randomizEd Trial of β-hydroxybUtyrate in prediabeteS)] included 18 adults [67% men, mean age = 55 y, mean BMI (kg/m2) = 28.4] with prediabetes (glycated hemoglobin between 5.7% and 6.4% and/or fasting plasma glucose between 100 and 125 mg/dL). Participants were randomly assigned to receive KEβHB-supplemented and placebo drinks in a crossover sequence (washout period of 7-10 d between the drinks). Blood samples were collected from 0 to 150 min, at intervals of 30 min. Paired-samples t tests were used to investigate the change in the outcome variables [β-hydroxybutyrate (βHB), glucose, and glucoregulatory peptides] after both drinks. Repeated measures analyses were conducted to determine the change in concentrations of the prespecified outcomes over time.

Results: Blood βHB concentrations increased to 3.5 mmol/L within 30 minutes after KEβHB supplementation. Plasma glucose AUC was significantly lower after KEβHB supplementation than after the placebo [mean difference (95% CI): -59 (-85.3, -32.3) mmol/L × min]. Compared with the placebo, KEβHB supplementation led to significantly greater AUCs for plasma insulin [0.237 (0.044, 0.429) nmol/L × min], C-peptide [0.259 (0.114, 0.403) nmol/L × min], and glucose-dependent insulinotropic peptide [0.243 (0.085, 0.401) nmol/L × min], with no significant differences in the AUCs for amylin, glucagon, and glucagon-like peptide 1.

Conclusions: Ingestion of the KEβHB-supplemented drink acutely increased the blood βHB concentrations and lowered the plasma glucose concentrations in adults with prediabetes. Further research is needed to investigate the dynamics of repeated ingestions of a KEβHB supplement by individuals with prediabetes, with a view to preventing new-onset diabetes. This trial was registered at www.clinicaltrials.gov as NCT03889210.
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http://dx.doi.org/10.1093/jn/nxaa417DOI Listing
April 2021

Analysis of Human Faecal Host Proteins: Responsiveness to 10-Week Dietary Intervention Modifying Dietary Protein Intake in Elderly Males.

Authors:
Jessica L Gathercole Anita J Grosvenor Erin Lee Ancy Thomas Cameron J Mitchell Nina Zeng Randall F D'Souza Farha Ramzan Pankaja Sharma Scott O Knowles Nicole C Roy Anders Sjödin Karl-Heinz Wagner Amber M Milan Sarah M Mitchell David Cameron-Smith

Front Nutr 2020 13;7:595905. Epub 2021 Jan 13.

Liggins Institute, University of Auckland, Auckland, New Zealand.

Faecal proteomics targeting biomarkers of immunity and inflammation have demonstrated clinical application for the identification of changes in gastrointestinal function. However, there are limited comprehensive analyses of the host faecal proteome and how it may be influenced by dietary factors. To examine this, the post-diet proteome of older males was analysed at the completion of a 10-week dietary intervention, either meeting the minimum dietary protein recommendations (RDA; = 9) or twice the recommended dietary allowance (2RDA, = 10). The host faecal proteome differed markedly between individuals, with only a small subset of proteins present in ≥ 60% of subjects (14 and 44 proteins, RDA and 2RDA, respectively, with only 7 common to both groups). No differences were observed between the diet groups on the profiles of host faecal proteins. Faecal proteins were detected from a wide range of protein classes, with high inter-individual variation and absence of obvious impact in response to diets with markedly different protein intake. This suggests that well-matched whole food diets with two-fold variation in protein intake maintained for 10 weeks have minimal impact on human faecal host proteins.
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http://dx.doi.org/10.3389/fnut.2020.595905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838370PMC
January 2021

MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis.

Authors:
Joseph C Reynolds Rochelle W Lai Jonathan S T Woodhead James H Joly Cameron J Mitchell David Cameron-Smith Ryan Lu Pinchas Cohen Nicholas A Graham Bérénice A Benayoun Troy L Merry Changhan Lee

Nat Commun 2021 01 20;12(1):470. Epub 2021 Jan 20.

Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, 90089, USA.

Healthy aging can be promoted by enhanced metabolic fitness and physical capacity. Mitochondria are chief metabolic organelles with strong implications in aging that also coordinate broad physiological functions, in part, using peptides that are encoded within their independent genome. However, mitochondrial-encoded factors that actively regulate aging are unknown. Here, we report that mitochondrial-encoded MOTS-c can significantly enhance physical performance in young (2 mo.), middle-age (12 mo.), and old (22 mo.) mice. MOTS-c can regulate (i) nuclear genes, including those related to metabolism and proteostasis, (ii) skeletal muscle metabolism, and (iii) myoblast adaptation to metabolic stress. We provide evidence that late-life (23.5 mo.) initiated intermittent MOTS-c treatment (3x/week) can increase physical capacity and healthspan in mice. In humans, exercise induces endogenous MOTS-c expression in skeletal muscle and in circulation. Our data indicate that aging is regulated by genes encoded in both of our co-evolved mitochondrial and nuclear genomes.
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http://dx.doi.org/10.1038/s41467-020-20790-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817689PMC
January 2021

Daily protein supplementation attenuates immobilization-induced blunting of postabsorptive muscle mTORC1 activation in middle-aged men.

Authors:
Nina Zeng Randall F D'Souza Caitlin L MacRae Vandre C Figueiredo Chantal A Pileggi James F Markworth Troy L Merry David Cameron-Smith Cameron J Mitchell

Am J Physiol Cell Physiol 2021 Apr 20;320(4):C591-C601. Epub 2021 Jan 20.

Liggins Institute, The University of Auckland, Auckland, New Zealand.

Disuse-induced muscle atrophy is accompanied by a blunted postprandial response of the mammalian target of rapamycin complex 1 (mTORC1) pathway. Conflicting observations exist as to whether postabsorptive mTORC1 pathway activation is also blunted by disuse and plays a role in atrophy. It is unknown whether changes in habitual protein intake alter mTORC1 regulatory proteins and how they may contribute to the development of anabolic resistance. The primary objective of this study was to characterize the downstream responsiveness of skeletal muscle mTORC1 activation and its upstream regulatory factors, following 14 days of lower limb disuse in middle-aged men (45-60 yr). The participants were further randomized to receive daily supplementation of 20 g/d of protein ( = 12; milk protein concentrate) or isocaloric carbohydrate placebo ( = 13). Immobilization reduced postabsorptive skeletal muscle phosphorylation of the mTORC1 downstream targets, 4E-BP1, P70S6K, and ribosomal protein S6 (RPS6), with phosphorylation of the latter two decreasing to a greater extent in the placebo, compared with the protein supplementation groups (37% ± 13% vs. 14% ± 11% and 38% ± 20% vs. 25% ± 8%, respectively). Sestrin2 protein was also downregulated following immobilization irrespective of supplement group, despite a corresponding increase in its mRNA content. This decrease in Sestrin2 protein was negatively correlated with the immobilization-induced change in the in silico-predicted regulator miR-23b-3p. No other measured upstream proteins were altered by immobilization or supplementation. Immobilization downregulated postabsorptive mTORC1 pathway activation, and 20 g/day of protein supplementation attenuated the decrease in phosphorylation of targets regulating muscle protein synthesis.
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http://dx.doi.org/10.1152/ajpcell.00284.2020DOI Listing
April 2021

Double-blind RCT of fish oil supplementation in pregnancy and lactation to improve the metabolic health in children of mothers with overweight or obesity during pregnancy: study protocol.

Authors:
Vidit V Satokar Wayne S Cutfield José G B Derraik Matire Harwood Karaponi Okasene-Gafa Kathryn Beck David Cameron-Smith Justin M O'Sullivan Gerhard Sundborn Shikha Pundir R Preston Mason Benjamin B Albert

BMJ Open 2020 12 15;10(12):e041015. Epub 2020 Dec 15.

Liggins Institute, University of Auckland, Auckland, New Zealand

Introduction: Maternal obesity during pregnancy is associated with adverse changes in body composition and metabolism in the offspring. We hypothesise that supplementation during pregnancy of overweight and obese women may help prevent the development of greater adiposity and metabolic dysfunction in children. Previous clinical trials investigating fish oil supplementation in pregnancy on metabolic outcomes and body composition of the children have not focused on the pregnancies of overweight or obese women.

Methods And Analysis: A double-blind randomised controlled trial of fish oil (providing 3 g/day of n-3 polyunsaturated fatty acids) versus an equal volume of olive oil (control) taken daily from recruitment until birth, and in breastfeeding mothers, further continued for 3 months post partum. Eligible women will have a singleton pregnancy at 12-20 weeks' gestation and be aged 18-40 years with body mass index ≥25 kg/m at baseline. We aim to recruit a minimum of 128 participants to be randomised 1:1. Clinical assessments will be performed at baseline and 30 weeks of pregnancy, including anthropometric measurements, fasting metabolic markers, measures of anxiety, physical activity, quality of life and dietary intake. Subsequent assessments will be performed when the infant is 2 weeks, 3 months and 12 months of age for anthropometry, body composition (dual-energy X-ray absorptiometry (DXA)) and blood sampling. The primary outcome of the study is a between-group difference in infant percentage body fatness, assessed by DXA, at 2 weeks of age. Secondary outcomes will include differences in anthropometric measures at each time point, percentage body fat at 3 and 12 months and homeostatic model assessment of insulin resistance at 3 months. Statistical analysis will be carried out on the principle of intention to treat.

Ethics And Dissemination: This trial was approved by the Northern A Health and Disabilities Ethics Committee, New Zealand Ministry of Health (17/NTA/154). Results will be published in a peer-reviewed journal.

Trial Registration Number: ACTRN12617001078347p; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2020-041015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745511PMC
December 2020

n - 3 Docosapentaenoic acid: the iceberg n - 3 fatty acid.

Authors:
Samaneh Ghasemi Fard David Cameron-Smith Andrew J Sinclair

Curr Opin Clin Nutr Metab Care 2021 Mar;24(2):134-138

Department of Nutrition, Dietetics and Food, Monash University.

Purpose Of Review: Docosapentaenoic acid (DPA) is a minor omega-3 fatty acid (FA) which has been frequently overlooked in lipid research. This review examines the biochemical and physiological outcomes of human trials which have used pure preparations of DPA (n - 3 DPA) and also recent developments in specialized proresolving lipid mediators (SPMs) derived from n - 3 DPA.

Recent Findings: There have been only been two human studies and eleven animal studies with pure n - 3 DPA. The doses of n - 3 DPA used in the human trials have been 1-2 g/day. n - 3 DPA abundance is increased in blood lipid fractions within 3-4 days of supplementation. n - 3 DPA has the potential for unique properties, with a greater similarity in biological functioning with docosahexaenoic acid (DHA), than eicosapentaenoic acid (EPA). Despite the typically low levels of n - 3 DPA in most tissue lipids relative to EPA and DHA, unique SPMs, such as resolvins, maresins and protectins of the n - 3 DPA type, are involved in resolution of inflammation and regulating immune function.

Summary: We suggest that measurement of blood levels of n - 3 DPA gives no indication of its broad biological roles, but that the true functionality of this enigmatic n - 3 polyunsaturated fatty acid (PUFA) remains obscure until more is known about the properties of the unique DPA-derived SPMs.
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http://dx.doi.org/10.1097/MCO.0000000000000722DOI Listing
March 2021

Association between Habitual Dietary Iron Intake and Glucose Metabolism in Individuals after Acute Pancreatitis.

Authors:
Wandia Kimita Xinye Li Juyeon Ko Sakina H Bharmal David Cameron-Smith Maxim S Petrov

Nutrients 2020 Nov 22;12(11). Epub 2020 Nov 22.

School of Medicine, University of Auckland, Auckland 1023, New Zealand.

Dietary intake of iron is known to be associated with impaired glucose metabolism. However, its involvement in derangements of glucose metabolism after acute pancreatitis (AP) is not completely understood. The aim was to investigate the association between dietary iron intake and markers of glucose metabolism in individuals after an attack of AP. Fasting blood samples were collected to analyse markers of glucose metabolism (fasting plasma glucose (FPG) and haemoglobin A1c (HbA1c)). The EPIC-Norfolk food frequency questionnaire was used to determine the habitual intake of dietary iron (total, haem, and non-haem). Multivariable linear regression analyses were conducted and six statistical models were built to adjust for covariates. A total of 109 individuals after AP were studied in a cross-sectional fashion. Total iron (β (95% confidence interval) = -0.19 (-0.35, -0.05); = 0.01 in the most adjusted model) and non-haem iron (β (95% confidence interval) = -0.19 (-0.33, -0.04); = 0.03 in the most adjusted model) were significantly associated with FPG, consistently in all adjusted model. Total iron and non-haem iron did not have consistent significant associations with HbA1c. Dietary haem iron intake was not associated with either FPG or HbA1c. Habitual intake of dietary iron is inversely associated with FPG in individuals after an attack of AP and may be involved in the pathogenesis of new-onset diabetes after pancreatitis. Prospective longitudinal studies are now warranted to unveil the specific mechanism underlying the involvement of dietary iron.
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http://dx.doi.org/10.3390/nu12113579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700518PMC
November 2020

Circulating Branched Chain Amino Acid Concentrations Are Higher in Dairy-Avoiding Females Following an Equal Volume of Sheep Milk Relative to Cow Milk: A Randomized Controlled Trial.

Authors:
Amber M Milan Linda M Samuelsson Aahana Shrestha Pankaja Sharma Li Day David Cameron-Smith

Front Nutr 2020 5;7:553674. Epub 2020 Nov 5.

The Liggins Institute, The University of Auckland, Auckland, New Zealand.

Intolerances to bovine dairy are a motivating factor in consumers seeking alternate-or replacement-dairy beverages and foods. Sheep milk (SM) is an alternate dairy source, with greater protein, although similar amino acid composition compared to cow milk (CM). Studies are yet to address the appearance of circulating amino acids following consumption of SM, relative to CM, in humans. To clinically determine the appearance of branched chain amino acids, and other amino acids, in circulation in response to equal servings of SM and CM, in females who avoid dairy products. In a double-blinded, randomized, cross-over trial, 30 self-described dairy avoiding females (20-40 years) drank 650 mL of SM or CM that were reconstituted from the spray dried powders (30 and 25 g in 180 mL water, respectively) on separate occasions, following an overnight fast. After reconstitution, the energy and protein provided by SM was higher than for CM (2,140 vs. 1,649 kJ; 29.9 vs. 19.4 g protein); content of branched chain amino acids (BCAAs) were 10.5 and 6.5 mgmL, respectively. Blood samples were collected at fasting and at regular intervals over 5 h after milk consumption. Plasma amino acids were measured by HPLC. 80% of subjects self-identified as lactose intolerant, and the majority (47%) "avoided drinking milk" "most of the time". SM resulted in greater plasma appearance of BCAAs at 60 min (641.1 ± 16.3 vs. 563.5 ± 14.4 μmol·L; < 0.001) compared with CM. SM similarly resulted in elevated postprandial concentrations of the amino acids lysine, methionine, and proline, particularly at 240 min (time × milk interactions = 0.011, 0.017, and = 0.002, respectively). Postprandial increases in plasma alanine concentrations were sustained to 120 min after CM (time × milk interaction = 0.001) but not after SM, despite greater quantities provided by SM. SM is a rich source of protein, and relative to CM, provides a greater quantity of BCAAs, with a corresponding elevation of the postprandial circulating BCAA response. SM is therefore a possible dairy alternative of benefit to those who need to increase total protein intake or for individuals with heightened protein requirements. : https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=375324, identifier U1111-1209-7768.
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http://dx.doi.org/10.3389/fnut.2020.553674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678490PMC
November 2020

Ribosome biogenesis and degradation regulate translational capacity during muscle disuse and reloading.

Authors:
Vandré C Figueiredo Randall F D'Souza Douglas W Van Pelt Marcus M Lawrence Nina Zeng James F Markworth Sally D Poppitt Benjamin F Miller Cameron J Mitchell John J McCarthy Esther E Dupont-Versteegden David Cameron-Smith

J Cachexia Sarcopenia Muscle 2021 Feb 24;12(1):130-143. Epub 2020 Nov 24.

Liggins Institute, The University of Auckland, Auckland, New Zealand.

Background: Translational capacity (i.e. ribosomal mass) is a key determinant of protein synthesis and has been associated with skeletal muscle hypertrophy. The role of translational capacity in muscle atrophy and regrowth from disuse is largely unknown. Therefore, we investigated the effect of muscle disuse and reloading on translational capacity in middle-aged men (Study 1) and in rats (Study 2).

Methods: In Study 1, 28 male participants (age 50.03 ± 3.54 years) underwent 2 weeks of knee immobilization followed by 2 weeks of ambulatory recovery and a further 2 weeks of resistance training. Muscle biopsies were obtained for measurement of total RNA and pre-ribosomal (r)RNA expression, and vastus lateralis cross-sectional area (CSA) was determined via peripheral quantitative computed tomography. In Study 2, male rats underwent hindlimb suspension (HS) for either 24 h (HS 24 h, n = 4) or 7 days (HS 7d, n = 5), HS for 7 days followed by 7 days of reloading (Rel, n = 5) or remained as ambulatory weight bearing (WB, n = 5) controls. Rats received deuterium oxide throughout the study to determine RNA synthesis and degradation, and mTORC1 signalling pathway was assessed.

Results: Two weeks of immobilization reduced total RNA concentration (20%) and CSA (4%) in men (both P ≤ 0.05). Ambulatory recovery restored total RNA concentration to baseline levels and partially restored muscle CSA. Total RNA concentration and 47S pre-rRNA expression increased above basal levels after resistance training (P ≤ 0.05). In rats, RNA synthesis was 30% lower while degradation was ~400% higher in HS 7d in soleus and plantaris muscles compared with WB (P ≤ 0.05). mTORC1 signalling was lower in HS compared with WB as was 47S pre-rRNA (P ≤ 0.05). With reloading, the aforementioned parameters were restored to WB levels while RNA degradation was suppressed (P ≤ 0.05).

Conclusions: Changes in RNA concentration following muscle disuse and reloading were associated with changes in ribosome biogenesis and degradation, indicating that both processes are important determinants of translational capacity. The pre-clinical data help explain the reduced translational capacity after muscle immobilization in humans and demonstrate that ribosome biogenesis and degradation might be valuable therapeutic targets to maintain muscle mass during disuse.
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http://dx.doi.org/10.1002/jcsm.12636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890271PMC
February 2021

Circulatory and Urinary B-Vitamin Responses to Multivitamin Supplement Ingestion Differ between Older and Younger Adults.

Authors:
Pankaja Sharma Soo Min Han Nicola Gillies Eric B Thorstensen Michael Goy Matthew P G Barnett Nicole C Roy David Cameron-Smith Amber M Milan

Nutrients 2020 Nov 17;12(11). Epub 2020 Nov 17.

The Liggins Institute, University of Auckland, Auckland 1023, New Zealand.

Multivitamin and mineral (MVM) supplements are frequently used amongst older populations to improve adequacy of micronutrients, including B-vitamins, but evidence for improved health outcomes are limited and deficiencies remain prevalent. Although this may indicate poor efficacy of supplements, this could also suggest the possibility for altered B-vitamin bioavailability and metabolism in older people. This open-label, single-arm acute parallel study, conducted at the Liggins Institute Clinical Research Unit in Auckland, compared circulatory and urinary B-vitamer responses to MVM supplementation in older (70.1 ± 2.7 y, = 10 male, = 10 female) compared to younger (24.2 ± 2.8 y, = 10 male, = 10 female) participants for 4 h after the ingestion of a single dose of a commercial MVM supplement and standardized breakfast. Older adults had a lower area under the curve (AUC) of postprandial plasma pyridoxine ( = 0.02) and pyridoxal-5'phosphate ( = 0.03) forms of vitamin B but greater 4-pyridoxic acid AUC ( = 0.009). Urinary pyridoxine and pyridoxal excretion were higher in younger females than in older females (time × age × sex interaction, < 0.05). Older adults had a greater AUC increase in plasma thiamine ( = 0.01), riboflavin ( = 0.009), and pantothenic acid ( = 0.027). In older adults, there was decreased plasma responsiveness of the ingested (pyridoxine) and active (pyridoxal-5'phosphate) forms of vitamin B, which indicated a previously undescribed alteration in either absorption or subsequent metabolic interconversion. While these findings cannot determine whether acute B responsiveness is adequate, this difference may have potential implications for B function in older adults. Although this may imply higher B vitamin substrate requirements for older people, further work is required to understand the implications of postprandial differences in availability.
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http://dx.doi.org/10.3390/nu12113529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698360PMC
November 2020

Folate and Vitamin B-12 Status Is Associated With Bone Mineral Density and Hip Strength of Postmenopausal Chinese-Singaporean Women.

Authors:
Maria Kalimeri Francesca Leek Nan Xin Wang Huann Rong Koh Nicole C Roy David Cameron-Smith Marlena C Kruger Christiani Jeyakumar Henry John J Totman

JBMR Plus 2020 Oct 2;4(10):e10399. Epub 2020 Sep 2.

Clinical Imaging Research Centre, Yong Loo Lin School of Medicine National University of Singapore Republic of Singapore.

The role of micronutrients such as folate and vitamin B-12 in bone quality has been widely studied with conflicting results. Ethnicity seems to play a large role on nutrient intake, as diet varies across cultures. In this study, we examined the relationships of BMD, proximal femur strength, and bone resorption with plasma folate and vitamin B-12 in a cohort of 93 healthy postmenopausal women of Chinese-Singaporean descent. The parameters examined were areal (aBMD) and volumetric BMD (vBMD) of the proximal femur and the third lumbar vertebra (L3), total body aBMD, proximal femur bending, compressive and impact strength indices (composite strength indices) and circulating levels of C-telopeptide of type I collagen. Eighteen participants (19.4%) had aBMD in the osteoporotic range (osteoporosis group), 59 (63.4%) in the osteopenic range (osteopenia group), and the remaining 16 (17.2%) in the normal range (normal BMD group). Circulating folate levels were significantly higher in the normal BMD group compared with the osteoporosis group. Using linear regression analysis, we found that overall, aBMD and vBMD are positively associated with folate concentrations, whereas composite strength indices were positively associated with vitamin B-12 concentrations. These findings support the existing literature and suggest a link between levels of circulating folate/vitamin B-12 and BMD/bone strength in the cohort examined. Further investigation is needed to examine if individuals with inadequate circulating levels of these nutrients could decrease their risk for fragility fractures through better nutrition or vitamin supplementation. © 2020 The Authors. published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research © 2020 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbm4.10399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574704PMC
October 2020

Human Milk Glucocorticoid Levels Are Associated With Infant Adiposity and Head Circumference Over the First Year of Life.

Authors:
Shikha Pundir Zoya Gridneva Avinesh Pillai Eric B Thorstensen Clare R Wall Donna T Geddes David Cameron-Smith

Front Nutr 2020 11;7:166. Epub 2020 Sep 11.

Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (ASTAR), Singapore, Singapore.

Human milk (HM) is a complex and dynamic biological fluid, which contains appreciable concentrations of the glucocorticoids, cortisol and cortisone. Experimental studies in non-human primates suggest the HM glucocorticoids' impact on infant growth and body composition. In this current study, analysis is made of the relationships between HM glucocorticoid concentrations and the infant growth and development over the first year of life. HM was collected by lactating healthy women ( = 18), using a standardized protocol, at 2, 5, 9, and 12 months after childbirth. Cortisol and cortisone concentrations in the HM were measured using liquid chromatography mass spectrometry. Infant weight, length and head circumference were measured by standard protocols and percentage fat mass (% FM) determined by whole body bioimpedance. Cortisol and cortisone concentrations were unaltered over the analyzed lactation period (2-12 months), and were altered by infant sex. Although, HM cortisol was positively associated with infant percentage fat mass (% FM) ( = 0.008) and cortisone positively associated with infant head circumference ( = 0.01). For the first 12 months of life, the concentration of HM glucocorticoids levels was positively associated with infant adiposity (%FM) and head circumference. This preliminary evidence provides insight to a possible relationship between ingested HM glucocorticoids and infant body composition. Further studies are required to determine the mechanisms regulating HM glucocorticoids.
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http://dx.doi.org/10.3389/fnut.2020.00166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516011PMC
September 2020

Omega-3 fats in pregnancy: could a targeted approach lead to better metabolic health for children?

Authors:
Vidit V Satokar Wayne S Cutfield David Cameron-Smith Benjamin B Albert

Nutr Rev 2021 Apr;79(5):574-584

Liggins Institute, University of Auckland, Auckland, New Zealand.

The prevalence of childhood obesity is increasing worldwide, and the children of women who are obese during pregnancy are at greatest risk. This risk may be mediated by exaggeration of the normal insulin resistance of pregnancy. Omega-3 (n-3) fats are insulin sensitizing. Supplementation during pregnancy may reduce metabolic risk and adiposity in the children. Though results from animal studies are encouraging, completed clinical trials have not demonstrated this benefit. However, to our knowledge, previous studies have not targeted women who are overweight or obese while pregnant-the group at greatest risk for insulin resistance and most likely to benefit from n-3. In this narrative review, the importance of performing clinical trials restricted to women who are overweight or obese is discussed, as is the potential importance of n-3 dose, oil source and quality, and the timing of the intervention.
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http://dx.doi.org/10.1093/nutrit/nuaa071DOI Listing
April 2021

Blunted nutrient-response pathways in adipose tissue following high fat meals in men with metabolic syndrome: A randomized postprandial transcriptomic study.

Authors:
Aimee L Dordevic Susan L Coort Chris T Evelo Chiara Murgia Andrew J Sinclair Maxine P Bonham Amy E Larsen Petra Gran David Cameron-Smith

Clin Nutr 2021 Mar 27;40(3):1355-1366. Epub 2020 Aug 27.

Liggins Institute, University of Auckland, Auckland, New Zealand; The Riddet Institute, Massey University, Palmerston North, New Zealand; Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore.

Background: Excessive adipose tissue is central to disease burden posed by the Metabolic Syndrome (MetS). Whilst much is known of the altered transcriptomic regulation of adipose tissue under fasting conditions, little is known of the responses to high-fat meals.

Methods: Nineteen middle-aged males (mean ± SD 52.0 ± 4.6 years), consumed two isocaloric high-fat, predominately dairy-based or soy-based, breakfast meals. Abdominal subcutaneous adipose biopsies were collected after overnight fast (0 h) and 4 h following each meal. Global gene expression profiling was performed by microarray (Illumina Human WG-6 v3).

Results: In the fasted state, 13 genes were differently expressed between control and MetS adipose tissue (≥1.2 fold-difference, p < 0.05). In response to the meals, the control participants had widespread increases in genes related to cellular nutrient responses (≥1.2 fold-change, p < 0.05; 2444 & 2367 genes; dairy & soy, respectively). There was blunted response in the MetS group (≥1.2 fold-change, p < 0.05; 332 & 336 genes; dairy & soy, respectively).

Conclusions: In middle-aged males with MetS, a widespread suppression of the subcutaneous adipose tissue nutrient responsive gene expression suggests an inflexibility in the transcriptomic responsiveness to both high-fat meals.
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http://dx.doi.org/10.1016/j.clnu.2020.08.024DOI Listing
March 2021

Growth Factor Concentrations in Human Milk Are Associated With Infant Weight and BMI From Birth to 5 Years.

Authors:
Laura Galante Shikha Pundir Hanna Lagström Samuli Rautava Clare Marie Reynolds Amber Marie Milan David Cameron-Smith Mark Hedley Vickers

Front Nutr 2020 29;7:110. Epub 2020 Jul 29.

The Liggins Institute, University of Auckland, Auckland, New Zealand.

Human milk bioactives may play a role in infant health and development. Although the variability in their concentrations in milk is well-established, the impact of differential milk profiles on infant growth outcomes remains unclear. Thus, the aim of the present study was to investigate whether different concentrations of metabolic hormones are associated with different weight and BMI in infants beyond the first year of life. Milk samples at 2.6 (±0.4) months after birth and anthropometric measures at 13 months, 2, 3, and 5 years were collected as part of the Finnish STEPS cohort study from 501 mothers and the respective 507 infants. Leptin, adiponectin, insulin-like growth factor (IGF)-1 and cyclic glycine-proline (cGP) in milk were analyzed. Multiple regression models and a repeated measures mixed model were used to examine associations between milk hormone concentrations and weight and BMI z-scores across time, at each time-point, and weight gain from birth to each follow-up visit. All models were corrected for birth weight, infant sex, duration of exclusive and total breastfeeding, time of introduction of solid foods and maternal pre-pregnancy BMI. Higher milk IGF-1 was associated with higher weight at 13 months ( = 0.004) but lower weight at 3 ( = 0.011) and 5 years of age ( = 0.049). Higher cGP was associated with lower weight across the 5 years ( = 0.019) but with higher BMI at 5 years ( = 0.021). Leptin and adiponectin did not display associations with infant growth at this time. Sex interactions were also absent. Our results suggest that the interplay between human milk-borne IGF-1 and cGP is similar to that reported in other mammals and may have an important role in defining infant growth trajectories beyond the first year of life. Further research should explore the determinants and origins of these milk-borne compounds and evaluate their effect on infant growth and metabolism.
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http://dx.doi.org/10.3389/fnut.2020.00110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403458PMC
July 2020

Preterm human milk: associations between perinatal factors and hormone concentrations throughout lactation.

Authors:
Laura Galante Clare M Reynolds Amber M Milan Tanith Alexander Frank H Bloomfield David Cameron-Smith Shikha Pundir Mark H Vickers

Pediatr Res 2020 Jul 29. Epub 2020 Jul 29.

The Liggins Institute, University of Auckland, Auckland, New Zealand.

Background: Infants born moderate to late preterm constitute the majority of preterm births, yet guidelines for their nutritional care are unclear. Maternal milk is the most appropriate nutrition for these infants; however, its composition can be influenced by environmental factors. The present study therefore investigated perinatal predictors of human milk composition in a preterm cohort.

Methods: Milk was collected during the DIAMOND trial (DIfferent Approaches to Moderate and late preterm Nutrition: Determinants of feed tolerance, body composition and development) from 169 mothers of 191 infants at three time-points (5 and 10 days post partum and 4 months' corrected age). Leptin, adiponectin and insulin-like growth factor-1 (IGF-1) were analysed by enzyme-linked immunosorbent assay. Generalised mixed models were used to evaluate associations between milk composition and maternal/infant/perinatal factors.

Results: Most findings were independent of collection time-point. Gestational diabetes was associated with lower adiponectin. Higher adiponectin and lower leptin were associated with higher socioeconomic status, higher maternal education and ability to fully breastfeed at discharge from hospital. Higher leptin was associated with high perceived stress during hospital admission. Milk IGF-1 displayed sex-specific patterns in association with maternal social deprivation.

Conclusion: Maternal, infant and environmental factors during the perinatal period were associated with milk compositional profiles throughout lactation. Further clinical trials should investigate the impact of such changes in terms of long-term infant outcomes.

Impact: Human milk is the best nutrition for the infant. However, its composition may be susceptible to alterations determined by pathological conditions mother and infant may face throughout pregnancy and in the perinatal period.This study found that perinatal factors are associated with human milk composition from early to late lactation.If human milk composition throughout lactation is "programmed" during pregnancy or early lactation, infants who were exposed in utero to environmental insults may still be exposed to them during lactation. The impact of human milk compositional alteration on infant growth following perinatal pathological events requires further investigation.
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http://dx.doi.org/10.1038/s41390-020-1069-1DOI Listing
July 2020

The Effects of Cold Water Immersion and Active Recovery on Molecular Factors That Regulate Growth and Remodeling of Skeletal Muscle After Resistance Exercise.

Authors:
Jonathan M Peake James F Markworth Kristoffer Toldnes Cumming Sigve N Aas Llion A Roberts Truls Raastad David Cameron-Smith Vandre C Figueiredo

Front Physiol 2020 30;11:737. Epub 2020 Jun 30.

Liggins Institute, The University of Auckland, Auckland, New Zealand.

Regular postexercise cooling attenuates muscle hypertrophy, yet its effects on the key molecular factors that regulate muscle growth and remodeling are not well characterized. In the present study, nine men completed two sessions of single-leg resistance exercise on separate days. On 1 day, they sat in cold water (10°C) up to their waist for 10 min after exercise. On the other day, they exercised at a low intensity for 10 min after exercise. Muscle biopsies were collected from the exercised leg before, 2, 24, and 48 h after exercise in both trials. These muscle samples were analyzed to evaluate changes in genes and proteins involved in muscle growth and remodeling. Muscle-specific RING finger 1 mRNA increased at 2 h after both trials ( < 0.05), while insulin-like growth factor (IGF)-1 Ec, IGF-1 receptor, growth arrest and DNA damage-inducible protein 45, collagen type I alpha chain A, collagen type III alpha chain 1, laminin and tissue inhibitor of metallopeptidase 1 mRNA increased 24-48 h after both trials ( < 0.05). By contrast, atrogin-1 mRNA decreased at all time points after both trials ( < 0.05). Protein expression of tenascin C increased 2 h after the active recovery trial ( < 0.05), whereas FoxO3a protein expression decreased after both trials ( < 0.05). Myostatin mRNA and ubiquitin protein expression did not change after either trial. These responses were not significantly different between the trials. The present findings suggest that regular cold water immersion attenuates muscle hypertrophy independently of changes in factors that regulate myogenesis, proteolysis and extracellular matrix remodeling in muscle after exercise.
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http://dx.doi.org/10.3389/fphys.2020.00737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339943PMC
June 2020

Differences in Compositions of Gut Bacterial Populations and Bacteriophages in 5-11 Year-Olds Born Preterm Compared to Full Term.

Authors:
Thilini N Jayasinghe Tommi Vatanen Valentina Chiavaroli Sachin Jayan Elizabeth J McKenzie Evelien Adriaenssens José G B Derraik Cameron Ekblad William Schierding Malcolm R Battin Eric B Thorstensen David Cameron-Smith Elizabeth Forbes-Blom Paul L Hofman Nicole C Roy Gerald W Tannock Mark H Vickers Wayne S Cutfield Justin M O'Sullivan

Front Cell Infect Microbiol 2020 16;10:276. Epub 2020 Jun 16.

Liggins Institute, University of Auckland, Auckland, New Zealand.

Preterm infants are exposed to major perinatal, post-natal, and early infancy events that could impact on the gut microbiome. These events include infection, steroid and antibiotic exposure, parenteral nutrition, necrotizing enterocolitis, and stress. Studies have shown that there are differences in the gut microbiome during the early months of life in preterm infants. We hypothesized that differences in the gut microbial composition and metabolites in children born very preterm persist into mid-childhood. Participants were healthy prepubertal children aged 5-11 years who were born very preterm (≤32 weeks of gestation; = 51) or at term (37-41 weeks; = 50). We recorded the gestational age, birth weight, mode of feeding, mode of birth, age, sex, and the current height and weight of our cohort. We performed a multi'omics [i.e., 16S rRNA amplicon and shotgun metagenomic sequencing, SPME-GCMS (solid-phase microextraction followed by gas chromatography-mass spectrometry)] analysis to investigate the structure and function of the fecal microbiome (as a proxy of the gut microbiota) in our cross-sectional cohort. Children born very preterm were younger (7.8 vs. 8.3 years; = 0.034), shorter [height-standard deviation score (SDS) 0.31 vs. 0.92; = 0.0006) and leaner [BMI (body mass index) SDS -0.20 vs. 0.29; < 0.0001] than the term group. Children born very preterm had higher fecal calprotectin levels, decreased fecal phage richness, lower plasma arginine, lower fecal branched-chain amino acids and higher fecal volatile (i.e., 3-methyl-butanoic acid, butyrolactone, butanoic acid and pentanoic acid) profiles. The bacterial microbiomes did not differ between preterm and term groups. We speculate that the observed very preterm-specific changes were established in early infancy and may impact on the capacity of the very preterm children to respond to environmental changes.
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http://dx.doi.org/10.3389/fcimb.2020.00276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7309444PMC
June 2020

Evaluation of breath, plasma, and urinary markers of lactose malabsorption to diagnose lactase non-persistence following lactose or milk ingestion.

Authors:
Aahana Shrestha Matthew P G Barnett Jo K Perry David Cameron-Smith Amber M Milan

BMC Gastroenterol 2020 Jun 29;20(1):204. Epub 2020 Jun 29.

The Liggins Institute, The University of Auckland, Auckland, New Zealand.

Background: Adult lactase non-persistence (LNP) is due to low lactase expression, resulting in lactose malabsorption (LM). LNP is a genetic trait, but is typically determined by LM markers including breath H, blood glucose, and urinary galactose after a lactose tolerance test. Known validity of these markers using milk is limited, despite being common practice. Compositional variation, such as β-casein variants, in milk may impact diagnostic efficacy. This study aimed to evaluate the diagnostic accuracy to detect LNP using these commonly measured LM markers after both lactose and milk challenges.

Methods: Fourty healthy young women were challenged with 50 g lactose then randomized for separate cross-over visits to ingest 750 mL milk (37.5 g lactose) as conventional (both A1 and A2 β-casein) and A1 β-casein-free (a2 Milk™) milk. Blood, breath and urine were collected prior to and up to 3 h following each challenge. The presence of C/T and G/A polymorphisms, determined by restriction fragment length polymorphism, was used as the diagnostic reference for LNP.

Results: Genetic testing identified 14 out of 40 subjects as having LNP (C/C and G/G). All three LM markers (breath H, plasma glucose and urinary galactose/creatinine) discriminated between lactase persistence (LP) and LNP following lactose challenge with an area under the receiver operating characteristic (ROC) curve (AUC) of 1.00, 0.75 and 0.73, respectively. Plasma glucose and urinary galactose/creatinine were unreliable (AUC < 0.70) after milk ingestion. The specificity of breath H remained high (100%) when milk was used, but sensitivity was reduced with conventional (92.9%) and a2 Milk™ (78.6%) compared to lactose (sensitivities adjusted for lactose content). The breath H optimal cut-off value was lower with a2 Milk™ (13 ppm) than conventional milk (21 ppm). Using existing literature cut-off values the sensitivity and specificity of breath H was greater than plasma glucose to detect LNP following lactose challenge whereas values obtained for urinary galactose/creatinine were lower than the existing literature cut-offs.

Conclusion: This study showed accurate diagnosis of LNP by breath H irrespective of the substrate used, although the diagnostic threshold may vary depending on the lactose substrate or the composition of the milk.

Trial Registration: ACTRN12616001694404 . Registered prospectively on December 9, 2016.
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http://dx.doi.org/10.1186/s12876-020-01352-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325051PMC
June 2020

Short-term high-intensity interval training exercise does not affect gut bacterial community diversity or composition of lean and overweight men.

Authors:
Elizabeth A Rettedal Julia M E Cree Shannon E Adams Caitlin MacRae Paula M L Skidmore David Cameron-Smith Nicholas Gant Cherie Blenkiron Troy L Merry

Exp Physiol 2020 08 17;105(8):1268-1279. Epub 2020 Jun 17.

Human Nutrition Unit, School of Biological Sciences, The University of Auckland, Auckland, New Zealand.

New Findings: What is the central question of this study? Does short-term high-intensity interval training alter the composition of the microbiome and is this associated with exercise-induced improvements in cardiorespiratory fitness and insulin sensitivity? What is the main finding and its importance? Although high-intensity interval training increased insulin sensitivity and cardiovascular fitness, it did not alter the composition of the microbiome. This suggests that changes in the composition of the microbiome that occur with prolonged exercise training might be in response to changes in metabolic health rather than driving exercise training-induced adaptations.

Abstract: Regular exercise reduces the risk of metabolic diseases, and the composition of the gut microbiome has been associated with metabolic function. We investigated whether short-term high-intensity interval training (HIIT) altered the diversity and composition of the bacterial community and whether there were associations with markers of insulin sensitivity or aerobic fitness. Cardiorespiratory fitness ( ) and body composition (dual energy X-ray absorptiometry scan) were assessed and faecal and fasted blood samples collected from 14 lean (fat mass 21 ± 2%, aged 29 ± 2 years) and 15 overweight (fat mass 33 ± 2%, aged 31 ± 2 years) men before and after 3 weeks of HIIT training (8-12 × 60 s cycle ergometer bouts at power output interspersed by 75 s rest, three times per week). Gut microbiome composition was analysed by 16S rRNA gene amplicon sequencing. The HIIT significantly increased the aerobic fitness of both groups (P < 0.001) and improved markers of insulin sensitivity (lowered fasted insulin and HOMA-IR; P < 0.001) in the overweight group. Despite differences in the abundance of several bacterial taxa being evident between the lean and overweight group, HIIT did not affect the overall bacterial diversity or community structure (α-diversity or β-diversity). No associations were found between the top 50 most abundant bacterial genera and cardiorespiratory fitness markers; however, significant associations (P < 0.05) were observed between the abundance of the bacterial species Coprococcus_3, Blautia, Lachnospiraceae_ge and Dorea and insulin sensitivity markers in the overweight group. Our results suggest that short-term HIIT does not greatly impact the overall composition of the gut microbiome, but that certain microbiome genera are associated with insulin sensitivity markers that were improved by HIIT in overweight participants.
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http://dx.doi.org/10.1113/EP088744DOI Listing
August 2020

Shared Regulatory Pathways Reveal Novel Genetic Correlations Between Grip Strength and Neuromuscular Disorders.

Authors:
Sreemol Gokuladhas William Schierding David Cameron-Smith Melissa Wake Emma L Scotter Justin O'Sullivan

Front Genet 2020 24;11:393. Epub 2020 Apr 24.

Liggins Institute, The University of Auckland, Auckland, New Zealand.

Muscle weakness is a common consequence of both aging (sarcopenia) and neuromuscular disorders (NMD). Whilst genome-wide association (GWA) studies have identified genetic variants associated with grip strength (GS; measure of muscle strength/weakness) and NMDs, including multiple sclerosis (MS), myasthenia gravis (MG) and amyotrophic lateral sclerosis (ALS), it is not known whether there are common mechanisms between these phenotypes. To examine this, we have integrated GS and NMD associated genetic variants (single nucleotide polymorphisms; SNPs) in a multimorbid analysis that leverages high-throughput chromatin interaction (Hi-C) data and expression quantitative trait loci data to identify target genes (i.e., SNP-mediated gene regulation). Biological pathways enriched by these genes were then identified using next-generation pathway enrichment analysis. Lastly, druggable genes were identified using drug gene interaction (DGI) database. We identified gene regulatory mechanisms associated with GS, MG, MS, and ALS. The SNPs associated with GS regulate a subset of genes that are also regulated by the SNPs of MS, MG, and ALS. Yet, we did not find any genes commonly regulated by all four phenotype associated SNPs. By contrast, we identified significant enrichment in three pathways (mTOR signaling, axon guidance, and alcoholism) that are commonly affected by the gene regulatory mechanisms associated with all four phenotypes. 13% of the genes we identified were known drug targets, and GS shares at least one druggable gene and pathway with each of the NMD phenotypes. We have identified significant biological overlaps between GS and NMD, demonstrating the potential for spatial genetic analysis to identify common mechanisms between potential multimorbid phenotypes. Collectively, our results form the foundation for a shift from a gene to a pathway-based approach to the rationale design of therapeutic interventions and treatments for NMD.
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http://dx.doi.org/10.3389/fgene.2020.00393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194178PMC
April 2020

High-intensity interval exercise increases humanin, a mitochondrial encoded peptide, in the plasma and muscle of men.

Authors:
Jonathan S T Woodhead Randall F D'Souza Christopher P Hedges Junxiang Wan Michael V Berridge David Cameron-Smith Pinchas Cohen Anthony J R Hickey Cameron J Mitchell Troy L Merry

J Appl Physiol (1985) 2020 05 9;128(5):1346-1354. Epub 2020 Apr 9.

Discipline of Nutrition, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.

Humanin is a small regulatory peptide encoded within the 16S ribosomal RNA gene () of the mitochondrial genome that has cellular cyto- and metabolo-protective properties similar to that of aerobic exercise training. Here we investigated whether acute high-intensity interval exercise or short-term high-intensity interval training (HIIT) impacted skeletal muscle and plasma humanin levels. Vastus lateralis muscle biopsies and plasma samples were collected from young healthy untrained men ( = 10, 24.5 ± 3.7 yr) before, immediately following, and 4 h following the completion of 10 × 60 s cycle ergometer bouts at V̇o power output (untrained). Resting and postexercise sampling was also performed after six HIIT sessions (trained) completed over 2 wk. Humanin protein abundance in muscle and plasma were increased following an acute high-intensity exercise bout. HIIT trended ( = 0.063) to lower absolute humanin plasma levels, without effecting the response in muscle or plasma to acute exercise. A similar response in the plasma was observed for the small humanin-like peptide 6 (SHLP6), but not SHLP2, indicating selective regulation of peptides encoded by MT-RNR2 gene. There was a weak positive correlation between muscle and plasma humanin levels, and contraction of isolated mouse EDL muscle increased humanin levels ~4-fold. The increase in muscle humanin levels with acute exercise was not associated with mRNA or mRNA levels (which decreased following acute exercise). Overall, these results suggest that humanin is an exercise-sensitive mitochondrial peptide and acute exercise-induced humanin responses in muscle are nontranscriptionally regulated and may partially contribute to the observed increase in plasma concentrations. Small regulatory peptides encoded within the mitochondrial genome (mitochondrial derived peptides) have been shown to have cellular cyto- and metabolo-protective roles that parallel those of exercise. Here we provide evidence that humanin and SHLP6 are exercise-sensitive mitochondrial derived peptides. Studies to determine whether mitochondrial derived peptides play a role in regulating exercise-induced adaptations are warranted.
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http://dx.doi.org/10.1152/japplphysiol.00032.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717117PMC
May 2020

Increased expression of the mitochondrial derived peptide, MOTS-c, in skeletal muscle of healthy aging men is associated with myofiber composition.

Authors:
Randall F D'Souza Jonathan S T Woodhead Christopher P Hedges Nina Zeng Junxiang Wan Hiroshi Kumagai Changhan Lee Pinchas Cohen David Cameron-Smith Cameron J Mitchell Troy L Merry

Aging (Albany NY) 2020 03 17;12(6):5244-5258. Epub 2020 Mar 17.

Discipline of Nutrition, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.

Mitochondria putatively regulate the aging process, in part, through the small regulatory peptide, mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) that is encoded by the mitochondrial genome. Here we investigated the regulation of MOTS-c in the plasma and skeletal muscle of healthy aging men. Circulating MOTS-c reduced with age, but older (70-81 y) and middle-aged (45-55 y) men had ~1.5-fold higher skeletal muscle MOTS-c expression than young (18-30 y). Plasma MOTS-c levels only correlated with plasma in young men, was associated with markers of slow-type muscle, and associated with improved muscle quality in the older group (maximal leg-press load relative to thigh cross-sectional area). Using small mRNA assays we provide evidence that MOTS-c transcription may be regulated independently of the full length 12S rRNA gene in which it is encoded, and expression is not associated with antioxidant response element (ARE)-related genes as previously seen in culture. Our results suggest that plasma and muscle MOTS-c are differentially regulated with aging, and the increase in muscle MOTS-c expression with age is consistent with fast-to-slow type muscle fiber transition. Further research is required to determine the molecular targets of endogenous MOTS-c in human muscle but they may relate to factors that maintain muscle quality.
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http://dx.doi.org/10.18632/aging.102944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138593PMC
March 2020

Comparable Postprandial Amino Acid and Gastrointestinal Hormone Responses to Beef Steak Cooked Using Different Methods: A Randomised Crossover Trial.

Authors:
Utpal K Prodhan Shikha Pundir Vic S-C Chiang Amber M Milan Matthew P G Barnett Greg C Smith James F Markworth Scott O Knowles David Cameron-Smith

Nutrients 2020 Jan 31;12(2). Epub 2020 Jan 31.

Liggins Institute, The University of Auckland, 85 Park Road, Grafton, Private Bag 92019, Auckland 1023, New Zealand.

Cooking changes the texture and tenderness of red meat, which may influence its digestibility, circulatory amino acids (AA) and gastrointestinal (GI) hormonal responses in consumers. In a randomised crossover intervention, healthy males ( = 12) consumed a beef steak sandwich, in which the beef was cooked by either a pan-fried (PF) or sous-vide (SV) method. Plasma AA were measured by ultrahigh performance liquid chromatography (UPLC), while plasma GI hormones were measured using a flow cytometric multiplex array. Following meat ingestion, the circulatory concentrations of some of the essential AA (all the branched-chain AA: leucine, isoleucine and valine; and threonine), some of the nonessential AA (glycine, alanine, tyrosine and proline) and some of the nonproteogenic AA (taurine, citrulline and ornithine) were increased from fasting levels by 120 or 180 min ( < 0.05). There were no differences in circulating AA concentrations between cooking methods. Likewise, of the measured GI hormones, glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) concentrations increased from fasting levels after consumption of the steak sandwich ( < 0.05), with no differences between the cooking methods. In the healthy male adults, protein digestion and circulating GI hormone responses to a beef-steak breakfast were unaltered by the different cooking methods.
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http://dx.doi.org/10.3390/nu12020380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071200PMC
January 2020

Sexually Dimorphic Associations between Maternal Factors and Human Milk Hormonal Concentrations.

Authors:
Laura Galante Hanna Lagström Mark H Vickers Clare M Reynolds Samuli Rautava Amber M Milan David Cameron-Smith Shikha Pundir

Nutrients 2020 Jan 6;12(1). Epub 2020 Jan 6.

The Liggins Institute, University of Auckland, Auckland 1023, New Zealand.

While human milk composition is characterised by marked dynamicity, we are far from having a clear picture of what factors drive this variation. Hormones in human milk are known to vary according to specific maternal phenotypes, but limited evidence shows the infant also has a role in determining milk composition. The present study aimed to investigate the interplay between maternal and infant characteristics in relation to human milk hormonal profile. In total, 501 human milk samples from mothers recruited in the Finnish STEPS cohort study (Steps to the healthy development) were analysed. Pre-pregnancy and pregnancy maternal data, socioeconomic status and infant characteristics at birth were collated. Leptin, adiponectin, insulin-like growth factor-1 and cyclic Glycine-Proline in milk were measured. Multivariate analysis of variance (MANOVA) and linear regression were utilised for statistical analysis. Sex-specific interactions with maternal factors were observed, as the infant sex mediated associations between gestational diabetes and milk adiponectin ( = 0.031), birth-mode and total protein ( = 0.003), maternal education and insulin-like growth factor-1: cyclic Glycine-Proline ratio ( = 0.035). Our results suggest that changes in human milk composition are associated with interactions between maternal and infant characteristics and pathophysiological factors. Future work should expand on these findings and further explore the link between hormonal profiles in human milk and infant outcomes.
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http://dx.doi.org/10.3390/nu12010152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019968PMC
January 2020

Impact of a High Protein Intake on the Plasma Metabolome in Elderly Males: 10 Week Randomized Dietary Intervention.

Authors:
Brenan Durainayagam Cameron J Mitchell Amber M Milan Nina Zeng Pankaja Sharma Sarah M Mitchell Farha Ramzan Scott O Knowles Anders Sjödin Karl-Heinz Wagner Nicole C Roy Karl Fraser David Cameron-Smith

Front Nutr 2019 6;6:180. Epub 2019 Dec 6.

Liggins Institute, University of Auckland, Auckland, New Zealand.

High protein diets may improve the maintenance of skeletal muscle mass in the elderly, although it remains less clear what broader impact such diets have on whole body metabolic regulation in the elderly. Non-targeted polar metabolomics analysis using HILIC HPLC-MS was used to profile the circulating plasma metabolome of elderly men ( = 31; 74.7 ± 4.0 years) who were randomized to consume for 10 weeks a diet designed to achieve either protein (RDA; 0.8·g·kg) or that doubled this recommend intake (2RDA; 1.6.g.kg). A limited number of plasma metabolites ( = 24) were significantly differentially regulated by the diet. These included markers of protein anabolism, which increased by the 2RDA diet, including; urea, creatine, and glutarylcarnitine. Whilst in response to the RDA diet; glutamine, glutamic acid, and proline were increased, relative to the 2RDA diet ( < 0.05). Metaboanalyst identified six major metabolic pathways to be influenced by the quantity of protein intake, most notably the arginine and proline pathways. Doubling of the recommended protein intake in older males over 10 weeks exerted only a limited impact on circulating metabolites, as determined by LC-MS. This metabolomic response was almost entirely due to increased circulating abundances of metabolites potentially indicative of altered protein anabolism, without evidence of impact on pathways for metabolic health. This trial was registered on 3rd March 2016 at the Australia New Zealand Clinical Trial Registry (www.anzctr.org.au) at ACTRN 12616000310460.
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http://dx.doi.org/10.3389/fnut.2019.00180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6910071PMC
December 2019

Acute responses of comprehensive gonadosteroids and corticosteroids to resistance exercise before and after 10 weeks of supervised strength training.

Authors:
Simon Walker Keijo Häkkinen Robert U Newton James F Markworth Shikha Pundir Guy G Haff David Cameron-Smith Anthony J Blazevich

Exp Physiol 2020 03 3;105(3):438-448. Epub 2020 Feb 3.

Centre for Exercise and Sports Science Research (CESSR), Edith Cowan University, Joondalup, WA, Australia.

New Findings: What is the central question of this study? Although acute responses of the principal gonadosteroid and corticosteroid hormones to resistance exercise are well documented, there is no information regarding how the key lower-concentration intermediary hormones respond and potentially influence these hormonal pathways. What is the main finding and its importance? This study provides evidence for cascading conversions of some gonadosteroids, and the data suggest that the testosterone concentration increases independently of these hormones. These findings challenge future studies to determine the exact physiological roles of the lower-concentration gonadosteroids and corticosteroids during and immediately after resistance exercise.

Abstract: Resistance training is a potent stimulus for muscle growth, and steroid hormones are known to play a role in this adaptation. However, very little is known about the acute exercise-induced gonadosteroid and corticosteroid hormone responses, including those of key lower-concentration intermediate hormones. The present study determined the acute responses of these steroid hormone families using quantitative ultra-high performance liquid chromatography tandem mass spectrometry after resistance exercise in strength-trained men. Venous and fingertip blood samples were obtained pre-, mid-, 5 min post- and 15 min post-resistance exercise, both before and after 10 weeks of supervised resistance training. The experimental resistance exercise sessions consisted of three sets of 10 repetitions of bilateral leg-press exercise and three sets of 10 repetitions of unilateral knee-extension exercise, with 2 and 1 min recovery between sets, respectively. Statistically significant (P < 0.05) increases in the concentration of hormones in the gonadosteroid [including dehydroepiandrosterone (DHEA), androstenedione, testosterone and estrone] and the corticosteroid (including cortisol, corticosterone and cortisone) families were demonstrated after both experimental resistance exercise sessions, irrespective of training status. Correlation analyses revealed relationships between the following hormones: (i) DHEA and androstenedione; (ii) DHEA and cortisol; (iii) androstenedione and estrone; and (iv) 11-deoxycortisol and cortisol. Testosterone appears to increase acutely and independently of other intermediary hormones after resistance exercise. In conclusion, lower-concentration intermediary gonadosteroids (e.g. estrone) and corticosteroids (e.g. corticosterone) respond robustly to resistance exercise in strength-trained men, although it seems that testosterone concentrations are regulated by factors other than the availability of precursor hormones and changes in plasma volume.
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http://dx.doi.org/10.1113/EP087995DOI Listing
March 2020

Comparison of the Acute Postprandial Circulating B-Vitamin and Vitamer Responses to Single Breakfast Meals in Young and Older Individuals: Preliminary Secondary Outcomes of a Randomized Controlled Trial.

Authors:
Pankaja Sharma Nicola Gillies Shikha Pundir Chantal A Pileggi James F Markworth Eric B Thorstensen David Cameron-Smith Amber M Milan

Nutrients 2019 Nov 28;11(12). Epub 2019 Nov 28.

The Liggins Institute, The University of Auckland, Auckland 1023, New Zealand.

B-vitamin deficiency is common in ageing populations either due to altered dietary habits or altered digestive and metabolic functions. There is limited data on the acute circulating concentrations of B-vitamins and their various forms (vitamers), following ingestion of realistic meals. This study compared the acute circulating B-vitamin and vitamer responses to either an energy-dense (ED) or a nutrient-dense (ND) breakfast meal, consumed in a randomized cross-over sequence, in older and younger adults ( = 15 and 15, aged 67.3 ± 1.5 and 22.7 ± 0.5 years (mean ± SEM), respectively). Eleven differing B-vitamins and vitamers were determined in plasma samples by ultra-high-performance liquid chromatography-tandem mass spectrometry, in the fasting and postprandial state (hourly for 5 h). While postprandial thiamine concentration increased following both meals, riboflavin increased only following a ND meal in both age groups. Many vitamins including nicotinic acid, pantothenic acid, pyridoxal, pyridoxamine, pyridoxal-5'phosphate, and 4-pyridoxic acid remained unaltered, and flavin mononucleotide (FMN), nicotinamide and nicotinuric acid concentrations reduced following both meals. Biological age and food composition had minimal impact on postprandial B-vitamin concentrations, yet the differences between the ED and ND meals for riboflavin highlight the importance of riboflavin intake to achieve adequacy.
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http://dx.doi.org/10.3390/nu11122893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950174PMC
November 2019