Publications by authors named "Keith Baar"

129 Publications

A 1-Month Ketogenic Diet Increased Mitochondrial Mass in Red Gastrocnemius Muscle, but Not in the Brain or Liver of Middle-Aged Mice.

Nutrients 2021 Jul 24;13(8). Epub 2021 Jul 24.

Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.

Alterations in markers of mitochondrial content with ketogenic diets (KD) have been reported in tissues of rodents, but morphological quantification of mitochondrial mass using transmission electron microscopy (TEM), the gold standard for mitochondrial quantification, is needed to further validate these findings and look at specific regions of interest within a tissue. In this study, red gastrocnemius muscle, the prefrontal cortex, the hippocampus, and the liver left lobe were used to investigate the impact of a 1-month KD on mitochondrial content in healthy middle-aged mice. The results showed that in red gastrocnemius muscle, the fractional area of both subsarcolemmal (SSM) and intermyofibrillar (IMM) mitochondria was increased, and this was driven by an increase in the number of mitochondria. Mitochondrial fractional area or number was not altered in the liver, prefrontal cortex, or hippocampus following 1 month of a KD. These results demonstrate tissue-specific changes in mitochondrial mass with a short-term KD and highlight the need to study different muscle groups or tissue regions with TEM to thoroughly determine the effects of a KD on mitochondrial mass.
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http://dx.doi.org/10.3390/nu13082533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8401881PMC
July 2021

A mutation in desmin makes skeletal muscle less vulnerable to acute muscle damage after eccentric loading in rats.

FASEB J 2021 09;35(9):e21860

Functional Molecular Biology Laboratory, Department of Physiology and Membrane Biology, University of California, Davis, California, USA.

Desminopathy is the most common intermediate filament disease in humans. The most frequent mutation causing desminopathy in patients is a R350P DES missense mutation. We have developed a rat model with an analogous mutation in R349P Des. To investigate the role of R349P Des in mechanical loading, we stimulated the sciatic nerve of wild-type littermates (WT) (n = 6) and animals carrying the mutation (MUT) (n = 6) causing a lengthening contraction of the dorsi flexor muscles. MUT animals showed signs of ongoing regeneration at baseline as indicated by a higher number of central nuclei (genotype: P < .0001). While stimulation did not impact central nuclei, we found an increased number of IgG positive fibers (membrane damage indicator) after eccentric contractions with both genotypes (stimulation: P < .01). Interestingly, WT animals displayed a more pronounced increase in IgG positive fibers with stimulation compared to MUT (interaction: P < .05). In addition to altered histology, molecular signaling on the protein level differed between WT and MUT. The membrane repair protein dysferlin decreased with eccentric loading in WT but increased in MUT (interaction: P < .05). The autophagic substrate p62 was increased in both genotypes with loading (stimulation: P < .05) but tended to be more elevated in WT (interaction: P = .05). Caspase 3 levels, a central regulator of apoptotic cell death, was increased with stimulation in both genotypes (stimulation: P < .01) but more so in WT animals (interaction: P < .0001). Overall, our data indicate that R349P Des rats have a lower susceptibility to structural muscle damage of the cytoskeleton and sarcolemma with acute eccentric loading.
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http://dx.doi.org/10.1096/fj.202100711RRDOI Listing
September 2021

Optimization of muscle cell culture media using nonlinear design of experiments.

Biotechnol J 2021 Aug 13:e2100228. Epub 2021 Aug 13.

Departments of Neurobiology, Physiology and Behavior and Physiology and Membrane Biology, University of California, Davis, California, USA.

Optimizing media for biological processes, such as those used in tissue engineering and cultivated meat production, is difficult due to the extensive experimentation required, number of media components, nonlinear and interactive responses, and the number of conflicting design objectives. Here we demonstrate the capacity of a nonlinear design-of-experiments (DOE) method to predict optimal media conditions in fewer experiments than a traditional DOE. The approach is based on a hybridization of a coordinate search for local optimization with dynamically adjusted search spaces and a global search method utilizing a truncated genetic algorithm using radial basis functions to store and model prior knowledge. Using this method, we were able to reduce the cost of muscle cell proliferation media while maintaining cell growth 48 h after seeding using 30 common components of typical commercial growth medium in fewer experiments than a traditional DOE (70 vs. 103). While we clearly demonstrated that the experimental optimization algorithm significantly outperforms conventional DOE, due to the choice of a 48 h growth assay weighted by medium cost as an objective function, these findings were limited to performance at a single passage, and did not generalize to growth over multiple passages. This underscores the importance of choosing objective functions that align well with process goals. GRAPHICAL ABSTRACT LAY SUMMARY: Layman's Summary of Work: In order to improve quality of muscle cell growth media, the effect of various metabolites were modeled using data collected in lab. The data is then used to suggest improvements to the medium using an algorithm called HND (hybrid nonlinear designer). This was done over multiple iterations to continually improve the media and did so using fewer experiments than traditional methods (70 vs. 103 experiments respectively).
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http://dx.doi.org/10.1002/biot.202100228DOI Listing
August 2021

Muscle-tendon cross talk during muscle wasting.

Am J Physiol Cell Physiol 2021 09 28;321(3):C559-C568. Epub 2021 Jul 28.

Functional Molecular Biology Laboratory, University of California, Davis, California.

In organisms from flies to mammals, the initial formation of a functional tendon is completely dependent on chemical signals from muscles (myokines). However, how myokines affect the maturation, maintenance, and regeneration of tendons as a function of age is completely unstudied. Here we discuss the role of four myokines-fibroblast growth factors (FGF), myostatin, the secreted protein acidic and rich in cysteine (SPARC) miR-29-in tendon development and hypothesize a role for these factors in the progressive changes in tendon structure and function as a result of muscle wasting (disuse, aging, and disease). Because of the close relationship between mechanical loading and muscle and tendon regulation, disentangling muscle-tendon cross talk from simple mechanical loading is experimentally quite difficult. Therefore, we propose an experimental framework that hopefully will be useful in demonstrating muscle-tendon cross talk in vivo. Though understudied, the promise of a better understanding of muscle-tendon cross talk is the development of new interventions that will improve tendon development, regeneration, and function throughout the lifespan.
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http://dx.doi.org/10.1152/ajpcell.00260.2021DOI Listing
September 2021

Sex differences in systemic bone and muscle loss following femur fracture in mice.

J Orthop Res 2021 Jun 3. Epub 2021 Jun 3.

Department of Orthopaedic Surgery, University of California Davis Health, Sacramento, California, USA.

Fracture induces systemic bone loss in mice and humans, and a first (index) fracture increases the risk of future fracture at any skeletal site more in men than women. The etiology of this sex difference is unknown, but fracture may induces a greater systemic bone loss response in men. Also sex differences in systemic muscle loss after fracture have not been examined. We investigated sex differences in systemic bone and muscle loss after transverse femur fracture in 3-month-old male and female C57BL/6 J mice. Whole-body and regional bone mineral content and density (BMC and BMD), trabecular and cortical bone microstructure, muscle contractile force, muscle mass, and muscle fiber size were quantified at multiple time points postfracture. Serum concentrations of inflammatory cytokines (IL-1β, IL-6, and TNF-α) were measured 1-day postfracture. One day postfracture, IL-6 and Il-1B were elevated in fracture mice of both sexes, but TNF-α was only elevated in male fracture mice. Fracture reduced BMC, BMD, and trabecular bone microstructural properties in both sexes 2 weeks postfracture, but declines were greater in males. Muscle contractile force, mass, and fiber size decreased primarily in the fractured limb at 2 weeks postfracture and females showed a trend toward greater muscle loss. Bone and muscle properties recovered by 6 weeks postfracture. Overall, postfracture systemic bone loss is greater in men, which may contribute to sex differences in subsequent fracture risk. In both sexes, muscle loss is primarily confined to the injured limb and fracture may induce greater inflammation in males.
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http://dx.doi.org/10.1002/jor.25116DOI Listing
June 2021

Maintenance of muscle mass in adult male mice is independent of testosterone.

PLoS One 2021 25;16(3):e0240278. Epub 2021 Mar 25.

Department of Internal Medicine, University of Iowa, Iowa City, IA, United States of America.

Testosterone is considered a potent anabolic agent in skeletal muscle with a well-established role in adolescent growth and development in males. However, the role of testosterone in the regulation of skeletal muscle mass and function throughout the lifespan has yet to be fully established. While some studies suggest that testosterone is important for the maintenance of skeletal muscle mass, an understanding of the role this hormone plays in young, adult, and old males with normal and low serum testosterone levels is lacking. We investigated the role testosterone plays in the maintenance of muscle mass by examining the effect of orchiectomy-induced testosterone depletion in C57Bl6 male mice at ages ranging from early postnatal through old age (1.5-, 5-, 12-, and 24-month old mice). Following 28 days of testosterone depletion, we assessed mass and fiber cross-sectional-area (CSA) of the tibialis anterior, gastrocnemius, and quadriceps muscles. In addition, we measured global rates of protein synthesis and degradation using the SuNSET method, western blots, and enzyme activity assays. Twenty-eight days of testosterone depletion resulted in reduced muscle mass in the two youngest cohorts, but had no effect in the two oldest cohorts. Mean CSA decreased only in the youngest cohort and only in the tibialis anterior muscle. Testosterone depletion resulted in a general increase in proteasome activity at all ages. No change in protein synthesis was detected at the terminal time point. These data suggest that within physiological serum concentrations, testosterone may not be critical for the maintenance of muscle mass in mature male mice; however, in young mice testosterone is crucial for normal growth.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240278PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993603PMC
August 2021

A ketogenic diet impacts markers of mitochondrial mass in a tissue specific manner in aged mice.

Aging (Albany NY) 2021 03 18;13(6):7914-7930. Epub 2021 Mar 18.

Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.

Declines in mitochondrial mass are thought to be a hallmark of mammalian aging, and a ketogenic diet (KD) may prevent the age-related decreases in mitochondrial content. The objective of this study was to investigate the impact of a KD on markers of mitochondrial mass. Mice were fed an isocaloric control diet (CD) or KD from 12 months of age. Tissues were collected after 1 month and 14 months of intervention, and a panel of commonly used markers of mitochondrial mass (mitochondrial enzyme activities and levels, mitochondrial to nuclear DNA ratio, and cardiolipin content) were measured. Our results showed that a KD stimulated activities of marker mitochondrial enzymes including citrate synthase, Complex I, and Complex IV in hindlimb muscle in aged mice. KD also increased the activity of citrate synthase and prevented an age-related decrease in Complex IV activity in aged brain. No other markers were increased in these tissues. Furthermore, the impacts of a KD on liver and kidney were mixed with no pattern indicative of a change in mitochondrial mass. In conclusion, results of the present study suggest that a KD induces tissue-specific changes in mitochondrial enzyme activities, or structure, rather than global changes in mitochondrial mass across tissues.
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http://dx.doi.org/10.18632/aging.202834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034930PMC
March 2021

The ketogenic diet preserves skeletal muscle with aging in mice.

Aging Cell 2021 04 6;20(4):e13322. Epub 2021 Mar 6.

Department of Neurobiology, Physiology and Behavior, University of California, Davis, CA, USA.

The causes of the decline in skeletal muscle mass and function with age, known as sarcopenia, are poorly understood. Nutrition (calorie restriction) interventions impact many cellular processes and increase lifespan and preserve muscle mass and function with age. As we previously observed an increase in life span and muscle function in aging mice on a ketogenic diet (KD), we aimed to investigate the effect of a KD on the maintenance of skeletal muscle mass with age and the potential molecular mechanisms of this action. Twelve-month-old mice were assigned to an isocaloric control or KD until 16 or 26 months of age, at which time skeletal muscle was collected for evaluating mass, morphology, and biochemical properties. Skeletal muscle mass was significantly greater at 26 months in the gastrocnemius of mice on the KD. This result in KD mice was associated with a shift in fiber type from type IIb to IIa fibers and a range of molecular parameters including increased markers of NMJ remodeling, mitochondrial biogenesis, oxidative metabolism, and antioxidant capacity, while decreasing endoplasmic reticulum (ER) stress, protein synthesis, and proteasome activity. Overall, this study shows the effectiveness of a long-term KD in mitigating sarcopenia. The diet preferentially preserved oxidative muscle fibers and improved mitochondrial and antioxidant capacity. These adaptations may result in a healthier cellular environment, decreasing oxidative and ER stress resulting in less protein turnover. These shifts allow mice to better maintain muscle mass and function with age.
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http://dx.doi.org/10.1111/acel.13322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045940PMC
April 2021

Cannabidiol Does Not Impair Anabolic Signaling Following Eccentric Contractions in Rats.

Int J Sport Nutr Exerc Metab 2021 Feb 23;31(2):93-100. Epub 2021 Feb 23.

University of California.

Cannabidiol (CBD) has proven clinical benefits in the treatment of seizures, inflammation, and pain. The recent legalization of CBD in many countries has caused increased interest in the drug as an over-the-counter treatment for athletes looking to improve recovery. However, no data on the effects of CBD on the adaptive response to exercise in muscle are available. To address this gap, we eccentrically loaded the tibialis anterior muscle of 14 rats, injected them with a vehicle (n = 7) or 100 mg/kg CBD (n = 7), and measured markers of injury, inflammation, anabolic signaling, and autophagy 18 hr later. Pro-inflammatory signaling through nuclear factor kappa B (NF-kB) (Ser536) increased with loading in both groups; however, the effect was significantly greater (36%) in the vehicle group (p < .05). Simultaneously, anabolic signaling through ribosomal protein S6 kinase beta-1 (S6K1) (Thr389) increased after eccentric contractions in both groups with no difference between vehicle and CBD (p = .66). The ribosomal protein S6 phosphorylation (240/244) increased with stimulation (p < .001) and tended to be higher in the CBD group (p = .09). The ubiquitin-binding protein p62 levels were not modulated by stimulation (p = .6), but they were 46% greater in the CBD compared with the vehicle group (p = .01). Although liver weight did not differ between the groups (p = .99) and levels of proteins associated with stress were similar, we did observe serious side effects in one animal. In conclusion, an acute dose of CBD decreased pro-inflammatory signaling in the tibialis anterior without blunting the anabolic response to exercise in rats. Future research should determine whether these effects translate to improved recovery without altering adaptation in humans.
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http://dx.doi.org/10.1123/ijsnem.2020-0270DOI Listing
February 2021

Considerations for the development of cost-effective cell culture media for cultivated meat production.

Compr Rev Food Sci Food Saf 2021 01 5;20(1):686-709. Epub 2020 Dec 5.

Department of Viticulture and Enology, University of California, Davis, California.

Innovation in cultivated meat development has been rapidly accelerating in recent years because it holds the potential to help attenuate issues facing production of dietary protein for a growing world population. There are technical obstacles still hindering large-scale commercialization of cultivated meat, of which many are related to the media that are used to culture the muscle, fat, and connective tissue cells. While animal cell culture media has been used and refined for roughly a century, it has not been specifically designed with the requirements of cultivated meat in mind. Perhaps the most common industrial use of animal cell culture is currently the production of therapeutic monoclonal antibodies, which sell for orders of magnitude more than meat. Successful production of cultivated meat requires media that is food grade with minimal cost, can regulate large-scale cell proliferation and differentiation, has acceptable sensory qualities, and is animal ingredient-free. Much insight into strategies for achieving media formulations with these qualities can be obtained from knowledge of conventional culture media applications and from the metabolic pathways involved in myogenesis and protein synthesis. In addition, application of principles used to optimize media for large-scale microbial fermentation processes producing lower value commodity chemicals and food ingredients can also be instructive. As such, the present review shall provide an overview of the current understanding of cell culture media as it relates to cultivated meat.
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http://dx.doi.org/10.1111/1541-4337.12678DOI Listing
January 2021

Adding exogenous biglycan or decorin improves tendon formation for equine peritenon and tendon proper cells in vitro.

BMC Musculoskelet Disord 2020 Sep 23;21(1):627. Epub 2020 Sep 23.

Department of Animal Science, University of California Davis, 2251 Meyer Hall, One Shields Ave, Davis, CA, 95616, USA.

Background: Tendon injuries amount to one of the leading causes of career-ending injuries in horses due to the inability for tendon to completely repair and the high reinjury potential. As a result, novel therapeutics are necessary to improve repair with the goal of decreasing leg lameness and potential reinjury. Small leucine-rich repeat proteoglycans (SLRPs), a class of regulatory molecules responsible for collagen organization and maturation, may be one such therapeutic to improve tendon repair. Before SLRP supplementation can occur in vivo, proper evaluation of the effect of these molecules in vitro needs to be assessed. The objective of this study was to evaluate the effectiveness of purified bovine biglycan or decorin on tendon proper and peritenon cell populations in three-dimensional tendon constructs.

Methods: Equine tendon proper or peritenon cell seeded fibrin three-dimensional constructs were supplemented with biglycan or decorin at two concentrations (5 nM or 25 nM). The functionality and ultrastructural morphology of the constructs were assessed using biomechanics, collagen content analysis, transmission electron microscopy (TEM), and gene expression by real time - quantitative polymerase chain reaction (RT-qPCR).

Results: SLRP supplementation affected both tendon proper and peritenon cells-seeded constructs. With additional SLRPs, material and tensile properties of constructs strengthened, though ultrastructural analyses indicated production of similar-sized or smaller fibrils. Overall expression of tendon markers was bolstered more in peritenon cells supplemented with either SLRP, while supplementation of SLRPs to TP cell-derived constructs demonstrated fewer changes in tendon and extracellular matrix markers. Moreover, relative to non-supplemented tendon proper cell-seeded constructs, SLRP supplementation of the peritenon cells showed increases in mechanical strength, material properties, and collagen content.

Conclusions: The SLRP-supplemented peritenon cells produced constructs with greater mechanical and material properties than tendon proper seeded constructs, as well as increased expression of matrix assembly molecules. These findings provide evidence that SLRPs should be further investigated for their potential to improve tendon formation in engineered grafts or post-injury.
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http://dx.doi.org/10.1186/s12891-020-03650-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513506PMC
September 2020

Generation of desminopathy in rats using CRISPR-Cas9.

J Cachexia Sarcopenia Muscle 2020 10 7;11(5):1364-1376. Epub 2020 Sep 7.

Department of Physiology and Membrane Biology, University of California, Davis, CA, USA.

Background: Desminopathy is a clinically heterogeneous muscle disease caused by over 60 different mutations in desmin. The most common mutation with a clinical phenotype in humans is an exchange of arginine to proline at position 350 of desmin leading to p.R350P. We created the first CRISPR-Cas9 engineered rat model for a muscle disease by mirroring the R350P mutation in humans.

Methods: Using CRISPR-Cas9 technology, Des c.1045-1046 (AGG > CCG) was introduced into exon 6 of the rat genome causing p.R349P. The genotype of each animal was confirmed via quantitative PCR. Six male rats with a mutation in desmin (n = 6) between the age of 120-150 days and an equal number of wild type littermates (n = 6) were used for experiments. Maximal plantar flexion force was measured in vivo and combined with the collection of muscle weights, immunoblotting, and histological analysis. In addition to the baseline phenotyping, we performed a synergist ablation study in the same animals.

Results: We found a difference in the number of central nuclei between desmin mutants (1 ± 0.4%) and wild type littermates (0.2 ± 0.1%; P < 0.05). While muscle weights did not differ, we found the levels of many structural proteins to be altered in mutant animals. Dystrophin and syntrophin were increased 54% and 45% in desmin mutants, respectively (P < 0.05). Dysferlin and Annexin A2, proteins associated with membrane repair, were increased two-fold and 32%, respectively, in mutants (P < 0.05). Synergist ablation caused similar increases in muscle weight between mutant and wild type animals, but changes in fibre diameter revealed that fibre hypertrophy in desmin mutants was hampered compared with wild type animals (P < 0.05).

Conclusions: We created a novel animal model for desminopathy that will be a useful tool in furthering our understanding of the disease. While mutant animals at an age corresponding to a preclinical age in humans show no macroscopic differences, microscopic and molecular changes are already present. Future studies should aim to further decipher those biological changes that precede the clinical progression of disease and test therapeutic approaches to delay disease progression.
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http://dx.doi.org/10.1002/jcsm.12619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567154PMC
October 2020

Optimisation and Validation of a Nutritional Intervention to Enhance Sleep Quality and Quantity.

Nutrients 2020 Aug 25;12(9). Epub 2020 Aug 25.

Departments of Neurobiology, Physiology & Behavior and Department of Physiology and Membrane Biology, University of California Davis School of Medicine, Davis, CA 95817, USA.

Background: Disturbed sleep may negatively influence physical health, cognitive performance, metabolism, and general wellbeing. Nutritional interventions represent a potential non-pharmacological means to increase sleep quality and quantity.

Objective: (1) Identify an optimal suite of nutritional ingredients and (2) validate the effects of this suite utilising polysomnography, and cognitive and balance tests.

Methods: The optimal and least optimal combinations of six ingredients were identified utilising 55 male participants and a Box-Behnken predictive model. To validate the model, 18 healthy, male, normal sleepers underwent three trials in a randomised, counterbalanced design: (1) optimal drink, (2) least optimal drink, or (3) placebo were provided before bed in a double-blinded manner. Polysomnography was utilised to measure sleep architecture. Cognitive performance, postural sway, and subjective sleep quality, were assessed 30 min after waking.

Results: The optimal drink resulted in a significantly shorter sleep onset latency (9.9 ± 12.3 min) when compared to both the least optimal drink (26.1 ± 37.4 min) and the placebo drink (19.6 ± 32.0 min). No other measures of sleep, cognitive performance, postural sway, and subjective sleep quality were different between trials.

Conclusion: A combination of ingredients, optimised to enhance sleep, significantly reduced sleep onset latency. No detrimental effects on sleep architecture, subjective sleep quality or next day performance were observed.
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http://dx.doi.org/10.3390/nu12092579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551573PMC
August 2020

Effect of a 12-week endurance training program on force transfer and membrane integrity proteins in lean, obese, and type 2 diabetic subjects.

Physiol Rep 2020 05;8(9):e14429

Exercise Physiology Laboratory, School of Kinesiology, Universidad Finis Terrae, Santiago, Chile.

The mechanisms accounting for the loss of muscle function with obesity and type 2 diabetes are likely the result of a combination of neural and muscular factors. One muscular factor that is important, yet has received little attention, is the protein machinery involved in longitudinal and lateral force transmission. The purpose of this study was to compare the levels of force transfer and membrane integrity proteins before and after a 12-week endurance training program in lean, obese, and obese type 2 diabetic adults. Nineteen sedentary subjects (male = 8 and female = 11) were divided into three groups: Lean (n = 7; 50.3 ± 4.1 y; 69.1 ± 7.2 kg); Obese (n = 6; 49.8 ± 4.1 y; 92.9 ± 19.5 kg); and Obese with type 2 diabetes (n = 6; 51.5 ± 7.9 years; 88.9 ± 15.1 kg). Participants trained 150 min/week between 55% and 75% of VO for 12 weeks. Skeletal muscle biopsies were taken before and after the training intervention. Baseline dystrophin and muscle LIM protein levels were higher (~50% p < .01) in lean compared to obese and type 2 diabetic adults, while the protein levels of the remaining force transfer and membrane integrity proteins were similar between groups. After training, obese individuals decreased (-53%; p < .01) the levels of the muscle ankyrin repeat protein and lean individuals decreased dystrophin levels (-45%; p = .01), while the levels of the remaining force transfer and membrane integrity proteins were not affected by training. These results suggest that there are modest changes to force transfer and membrane integrity proteins in middle-aged individuals as a result of 12 weeks of lifestyle and training interventions.
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http://dx.doi.org/10.14814/phy2.14429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195556PMC
May 2020

Case report of an exercise training and nutritional intervention plan in a patient with A350P mutation in DES gene.

Clin Case Rep 2020 Feb 14;8(2):283-288. Epub 2020 Jan 14.

Universidad Finis Terrae Región Metropolitana Chile.

Performing a supplementation intervention with creatine and protein, in conjunction with low-intensity endurance and resistance exercise is safe and has a positive effect on the quality of life in a patient with desminopathy.
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http://dx.doi.org/10.1002/ccr3.2607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044380PMC
February 2020

Rehabilitation and nutrition protocols for optimising return to play from traditional ACL reconstruction in elite rugby union players: A case study.

J Sports Sci 2019 Aug 9;37(15):1794-1803. Epub 2019 Apr 9.

c Department of Neurobiology, Physiology, and Behaviour , University of California Davis , Davis, CA , USA.

Current nutrition and exercise focus during rehabilitation periods has been on reducing muscle atrophy associated with immobilisation. This case report outlines a best practice anterior cruciate ligament (ACL) rehabilitation programme undertaken by two professional rugby athletes, with the addition of an evidence-based supplementation (gelatine and vitamin C) and exercise protocol focused on collagenous tissue. Both players ruptured their left ACL and were repaired with a traditional hamstring graft. Players undertook a structured rehabilitation programme for 34 weeks before being clinically assessed ready to play. Players saw minimal changes in body composition in the early rehabilitation period (P1 - 0.8 kg; P2 - 0.4 kg). Leg lean mass reduced in both legs of Player 1 (Injured - 0.8 kg, Non-injured - 0.6 kg) at 17 weeks, with Player 2 only experiencing a loss of 0.3 kg of lean tissue in the injured leg. Both players returned to baseline body compositions after 24 weeks. Leg strength returned to a maximum at 24 and 15 weeks, respectively, with knee function returning to baseline by 30 weeks. This case report provides evidence that nutrition and rehabilitation programmes targeted at minimising the effects of disuse in both muscle and connective tissue may assist return to play after ACL injury.
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http://dx.doi.org/10.1080/02640414.2019.1594571DOI Listing
August 2019

Effects of Different Vitamin C-Enriched Collagen Derivatives on Collagen Synthesis.

Int J Sport Nutr Exerc Metab 2019 Sep;29(5):526-531

University of California Davis.

Nutritional strategies to improve connective tissue collagen synthesis have garnered significant interest, although the scientific validity of these interventions lags behind their hype. This study was designed to determine the effects of three forms of collagen on N-terminal peptide of procollagen and serum amino acid levels. A total of 10 recreationally active males completed a randomized double-blinded crossover design study consuming either placebo or 15 g of vitamin C-enriched gelatin or hydrolyzed collagen (HC), or gummy containing equal parts of gelatin and HC. Supplements were consumed 1 hr before 6 min of jump rope. Blood samples were collected immediately prior to supplement consumption and 4 hr after jump rope. A subset of blood samples (n = 4) was collected for amino acid analysis 1 hr after ingestion. Consumption of an equivalent dose of each supplement increased amino acids in the circulation similarly across all interventions. N-terminal peptide of procollagen levels tended to increase ∼20% from baseline in the gelatin and HC interventions but not the placebo or gummy. These results suggest that vitamin C-enriched gelatin and HC supplementation may improve collagen synthesis when taken 1 hr prior to exercise. However, large variability was observed, which precluded significance for any treatment.
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http://dx.doi.org/10.1123/ijsnem.2018-0385DOI Listing
September 2019

Effect of Estrogen on Musculoskeletal Performance and Injury Risk.

Front Physiol 2018 15;9:1834. Epub 2019 Jan 15.

Biomedical Engineering Graduate Group, University of California, Davis, Davis, CA, United States.

Estrogen has a dramatic effect on musculoskeletal function. Beyond the known relationship between estrogen and bone, it directly affects the structure and function of other musculoskeletal tissues such as muscle, tendon, and ligament. In these other musculoskeletal tissues, estrogen improves muscle mass and strength, and increases the collagen content of connective tissues. However, unlike bone and muscle where estrogen improves function, in tendons and ligaments estrogen decreases stiffness, and this directly affects performance and injury rates. High estrogen levels can decrease power and performance and make women more prone for catastrophic ligament injury. The goal of the current work is to review the research that forms the basis of our understanding how estrogen affects muscle, tendon, and ligament and how hormonal manipulation can be used to optimize performance and promote female participation in an active lifestyle at any age.
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http://dx.doi.org/10.3389/fphys.2018.01834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341375PMC
January 2019

Normal Ribosomal Biogenesis but Shortened Protein Synthetic Response to Acute Eccentric Resistance Exercise in Old Skeletal Muscle.

Front Physiol 2018 14;9:1915. Epub 2019 Jan 14.

Department of Physiology and Membrane Biology, University of California, Davis, Davis, CA, United States.

Anabolic resistance to feeding in aged muscle is well-characterized; however, whether old skeletal muscle is intrinsically resistant to acute mechanical loading is less clear. The aim of this study was to determine the impact of aging on muscle protein synthesis (MPS), ribosome biogenesis, and protein breakdown in skeletal muscle following a single bout of resistance exercise. Adult male F344/BN rats aged 10 (Adult) and 30 (Old) months underwent unilateral maximal eccentric contractions of the hindlimb. Precursor rRNA increased early post-exercise (6-18 h), preceding elevations in ribosomal mass at 48 h in Adult and Old; there were no age-related differences in these responses. MPS increased early post-exercise in both Adult and Old; however, at 48 h of recovery, MPS returned to baseline in Old but not Adult. This abbreviated protein synthesis response in Old was associated with decreased levels of IRS1 protein and increased BiP, CHOP and eIF2α levels. Other than these responses, anabolic signaling was similar in Adult and Old muscle in the acute recovery phase. Basal proteasome activity was lower in Old, and resistance exercise did not increase the activity of either the ATP-dependent or independent proteasome, or autophagy (Cathepsin L activity) in either Adult or Old muscle. We conclude that MPS and ribosome biogenesis in response to maximal resistance exercise in old skeletal muscle are initially intact; however, the MPS response is abbreviated in Old, which may be the result of ER stress and/or blunted exercise-induced potentiation of the MPS response to feeding.
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http://dx.doi.org/10.3389/fphys.2018.01915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339931PMC
January 2019

Nutrition for the Prevention and Treatment of Injuries in Track and Field Athletes.

Int J Sport Nutr Exerc Metab 2019 Mar 8;29(2):189-197. Epub 2019 Mar 8.

4 Université Côte d'Azur.

Injuries are an inevitable consequence of athletic performance with most athletes sustaining one or more during their athletic careers. As many as one in 12 athletes incur an injury during international competitions, many of which result in time lost from training and competition. Injuries to skeletal muscle account for over 40% of all injuries, with the lower leg being the predominant site of injury. Other common injuries include fractures, especially stress fractures in athletes with low energy availability, and injuries to tendons and ligaments, especially those involved in high-impact sports, such as jumping. Given the high prevalence of injury, it is not surprising that there has been a great deal of interest in factors that may reduce the risk of injury, or decrease the recovery time if an injury should occur: One of the main variables explored is nutrition. This review investigates the evidence around various nutrition strategies, including macro- and micronutrients, as well as total energy intake, to reduce the risk of injury and improve recovery time, focusing upon injuries to skeletal muscle, bone, tendons, and ligaments.
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http://dx.doi.org/10.1123/ijsnem.2018-0290DOI Listing
March 2019

Stress Relaxation and Targeted Nutrition to Treat Patellar Tendinopathy.

Authors:
Keith Baar

Int J Sport Nutr Exerc Metab 2019 07 1;29(4):453–457. Epub 2019 Jul 1.

1 University of California Davis.

Patellar tendinopathy is one of the most common afflictions in jumping sports. This case study outlines the rehabilitation of a professional basketball player diagnosed by magnetic resonance imaging (MRI) with a central core patellar tendinopathy within the proximal enthesis. The player undertook a nutrition and strength-based rehabilitation program combining gelatin ingestion and heavy isometric loading of the patellar tendon designed to produce significant stress relaxation as part of their competition schedule and a whole-body training plan. On follow-up one and a half years into the program an independent orthopedic surgeon declared the tendon normal on MRI. Importantly, the improved MRI results were associated with a decrease in pain and improved performance. This case study provides evidence that a nutritional intervention combined with a rehabilitation program that uses stress relaxation can improve clinical outcomes in elite athletes.
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http://dx.doi.org/10.1123/ijsnem.2018-0231DOI Listing
July 2019

Age-dependent bone loss and recovery during hindlimb unloading and subsequent reloading in rats.

BMC Musculoskelet Disord 2018 Jul 18;19(1):223. Epub 2018 Jul 18.

Biomedical Engineering Graduate Group, University of California Davis, Davis, CA, USA.

Background: Bone structure and strength are rapidly lost during conditions of decreased mechanical loading, and aged bones have a diminished ability to adapt to increased mechanical loading. This is a concern for older patients that experience periods of limited mobility or bed rest, but the acute effects of disuse on the bones of aged patients have not been thoroughly described. Previous animal studies have primarily examined the effect of mechanical unloading on young animals. Those that have studied aged animals have exclusively focused on bone loss during unloading and not bone recovery during subsequent reloading. In this study, we investigated the effect of decreased mechanical loading and subsequent reloading on bone using a hindlimb unloading model in Adult (9 month old) and Aged (28 month old) male rats.

Methods: Animals from both age groups were subjected to 14 days of hindlimb unloading followed by up to 7 days of reloading. Additional Aged rats were subjected to 7 days of forced treadmill exercise during reloading or a total of 28 days of reloading. Trabecular and cortical bone structure of the femur were quantified using ex vivo micro-computed tomography (μCT), and mechanical properties were quantified with mechanical testing.

Results: We found that Adult rats had substantially decreased trabecular bone volume fraction (BV/TV) following unloading (- 27%) while Aged animals did not exhibit significant bone loss following unloading. However, Aged animals had lower trabecular BV/TV after 3 days of reloading (- 20% compared to baseline), while trabecular BV/TV of Adult rats was not different from baseline values after 3 days of reloading. Trabecular BV/TV of Aged animals remained lower than control animals even with exercise during 7 days of reloading and after 28 days of reloading.

Conclusions: These data suggest that aged bone is less responsive to both increased and decreased mechanical loading, and that acute periods of disuse may leave older subjects with a long-term deficit in trabecular bone mass. These finding indicate the need for therapeutic strategies to improve the skeletal health of elderly patients during periods of disuse.
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http://dx.doi.org/10.1186/s12891-018-2156-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6052521PMC
July 2018

Alterations in the muscle force transfer apparatus in aged rats during unloading and reloading: impact of microRNA-31.

J Physiol 2018 07;596(14):2883-2900

Department of Neurobiology, Physiology and Behavior, University of California Davis, Davis, CA, USA.

Key Points: Force transfer is integral for maintaining skeletal muscle structure and function. One important component is dystrophin. There is limited understanding of how force transfer is impacted by age and loading. Here, we investigate the force transfer apparatus in muscles of adult and old rats exposed to periods of disuse and reloading. Our results demonstrate an increase in dystrophin protein during the reloading phase in the adult tibialis anterior muscle that is delayed in the old muscle. The consequence of this delay is an increased susceptibility towards contraction-induced muscle injury. Central to the lack of dystrophin protein is an increase in miR-31, a microRNA that inhibits dystrophin translation. In vivo electroporation with a miR-31 sponge led to increased dystrophin protein and decreased contraction-induced muscle injury in old skeletal muscle. Overall, our results detail the importance of the force transfer apparatus and provide new mechanisms for contraction-induced injury in ageing skeletal muscle.

Abstract: In healthy muscle, the dystrophin-associated glycoprotein complex (DGC), the integrin/focal adhesion complex, intermediate filaments and Z-line proteins transmit force from the contractile proteins to the extracellular matrix. How loading and age affect these proteins is poorly understood. The experiments reported here sought to determine the effect of ageing on the force transfer apparatus following muscle unloading and reloading. Adult (9 months) and old (28 months) rats were subjected to 14 days of hindlimb unloading and 1, 3, 7 and 14 days of reloading. The DGC complex, intermediate filament and Z-line protein and mRNA levels, as well as dystrophin-targeting miRNAs (miR-31, -146b and -374) were examined in the tibialis anterior (TA) and medial gastrocnemius muscles at both ages. There was a significant increase in dystrophin protein levels (2.79-fold) upon 3 days of reloading in the adult TA muscle that did not occur in the old rats (P ≤ 0.05), and the rise in dystrophin protein occurred independent of dystrophin mRNA. The disconnect between dystrophin protein and mRNA levels can partially be explained by age-dependent differences in miR-31. The impaired dystrophin response in aged muscle was followed by an increase in other force transfer proteins (β-dystroglycan, desmuslin and LIM) that was not sufficient to prevent membrane disruption and muscle injury early in the reloading period. Inserting a miR-31 sponge increased dystrophin protein and decreased contraction-induced injury in the TA (P ≤ 0.05). Collectively, these data suggest that increased miR-31 with age contributes to an impaired dystrophin response and increased muscle injury after disuse.
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http://dx.doi.org/10.1113/JP275833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6046073PMC
July 2018

Characterisation of L-Type Amino Acid Transporter 1 (LAT1) Expression in Human Skeletal Muscle by Immunofluorescent Microscopy.

Nutrients 2017 Dec 26;10(1). Epub 2017 Dec 26.

School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham B15 2TT, UK.

The branch chain amino acid leucine is a potent stimulator of protein synthesis in skeletal muscle. Leucine rapidly enters the cell via the L-Type Amino Acid Transporter 1 (LAT1); however, little is known regarding the localisation and distribution of this transporter in human skeletal muscle. Therefore, we applied immunofluorescence staining approaches to visualise LAT1 in wild type (WT) and LAT1 muscle-specific knockout (mKO) mice, in addition to basal human skeletal muscle samples. LAT1 positive staining was visually greater in WT muscles compared to mKO muscle. In human skeletal muscle, positive LAT1 staining was noted close to the sarcolemmal membrane (dystrophin positive staining), with a greater staining intensity for LAT1 observed in the sarcoplasmic regions of type II fibres (those not stained positively for myosin heavy-chain 1, Type II-25.07 ± 5.93, Type I-13.71 ± 1.98, < 0.01), suggesting a greater abundance of this protein in these fibres. Finally, we observed association with LAT1 and endothelial nitric oxide synthase (eNOS), suggesting LAT1 association close to the microvasculature. This is the first study to visualise the distribution and localisation of LAT1 in human skeletal muscle. As such, this approach provides a validated experimental platform to study the role and regulation of LAT1 in human skeletal muscle in response to various physiological and pathophysiological models.
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http://dx.doi.org/10.3390/nu10010023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5793251PMC
December 2017

A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice.

Cell Metab 2017 Sep;26(3):539-546.e5

Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, USA. Electronic address:

Calorie restriction, without malnutrition, has been shown to increase lifespan and is associated with a shift away from glycolysis toward beta-oxidation. The objective of this study was to mimic this metabolic shift using low-carbohydrate diets and to determine the influence of these diets on longevity and healthspan in mice. C57BL/6 mice were assigned to a ketogenic, low-carbohydrate, or control diet at 12 months of age and were either allowed to live their natural lifespan or tested for physiological function after 1 or 14 months of dietary intervention. The ketogenic diet (KD) significantly increased median lifespan and survival compared to controls. In aged mice, only those consuming a KD displayed preservation of physiological function. The KD increased protein acetylation levels and regulated mTORC1 signaling in a tissue-dependent manner. This study demonstrates that a KD extends longevity and healthspan in mice.
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http://dx.doi.org/10.1016/j.cmet.2017.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5609489PMC
September 2017

Selected In-Season Nutritional Strategies to Enhance Recovery for Team Sport Athletes: A Practical Overview.

Sports Med 2017 Nov;47(11):2201-2218

Gatorade Sports Science Institute, 617 West Main St., Barrington, IL, 60010, USA.

Team sport athletes face a variety of nutritional challenges related to recovery during the competitive season. The purpose of this article is to review nutrition strategies related to muscle regeneration, glycogen restoration, fatigue, physical and immune health, and preparation for subsequent training bouts and competitions. Given the limited opportunities to recover between training bouts and games throughout the competitive season, athletes must be deliberate in their recovery strategy. Foundational components of recovery related to protein, carbohydrates, and fluid have been extensively reviewed and accepted. Micronutrients and supplements that may be efficacious for promoting recovery include vitamin D, omega-3 polyunsaturated fatty acids, creatine, collagen/vitamin C, and antioxidants. Curcumin and bromelain may also provide a recovery benefit during the competitive season but future research is warranted prior to incorporating supplemental dosages into the athlete's diet. Air travel poses nutritional challenges related to nutrient timing and quality. Incorporating strategies to consume efficacious micronutrients and ingredients is necessary to support athlete recovery in season.
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http://dx.doi.org/10.1007/s40279-017-0759-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5633631PMC
November 2017

Treatment of Ligament Constructs with Exercise-conditioned Serum: A Translational Tissue Engineering Model.

J Vis Exp 2017 06 11(124). Epub 2017 Jun 11.

Department of Neurobiology, Physiology, and Behavior, University of California, Davis; Faculty of Kinesiology and Physical Education, University of Toronto.

In vitro experiments are essential to understand biological mechanisms; however, the gap between monolayer tissue culture and human physiology is large, and translation of findings is often poor. Thus, there is ample opportunity for alternative experimental approaches. Here we present an approach in which human cells are isolated from human anterior cruciate ligament tissue remnants, expanded in culture, and used to form engineered ligaments. Exercise alters the biochemical milieu in the blood such that the function of many tissues, organs and bodily processes are improved. In this experiment, ligament construct culture media was supplemented with experimental human serum that has been 'conditioned' by exercise. Thus the intervention is more biologically relevant since an experimental tissue is exposed to the full endogenous biochemical milieu, including binding proteins and adjunct compounds that may be altered in tandem with the activity of an unknown agent of interest. After treatment, engineered ligaments can be analyzed for mechanical function, collagen content, morphology, and cellular biochemistry. Overall, there are four major advantages versus traditional monolayer culture and animal models, of the physiological model of ligament tissue that is presented here. First, ligament constructs are three-dimensional, allowing for mechanical properties (i.e., function) such as ultimate tensile stress, maximal tensile load, and modulus, to be quantified. Second, the enthesis, the interface between boney and sinew elements, can be examined in detail and within functional context. Third, preparing media with post-exercise serum allows for the effects of the exercise-induced biochemical milieu, which is responsible for the wide range of health benefits of exercise, to be investigated in an unbiased manner. Finally, this experimental model advances scientific research in a humane and ethical manner by replacing the use of animals, a core mandate of the National Institutes of Health, the Center for Disease Control, and the Food and Drug Administration.
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http://dx.doi.org/10.3791/55339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5608388PMC
June 2017
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