Publications by authors named "Rizwan Qaisar"

26 Publications

  • Page 1 of 1

Reduced sarcoplasmic reticulum Ca ATPase activity underlies skeletal muscle wasting in asthma.

Life Sci 2021 May 3;273:119296. Epub 2021 Mar 3.

Department of Biochemistry, Gomal Medical College, Dera Ismail Khan, Pakistan.

Aims: Skeletal muscle mass and strength are reduced in asthma and contribute to compromised functional capacity in asthmatic patients. However, an effective pharmacological intervention remains elusive, partly because molecular mechanisms dictating muscle decline in asthma are not known.

Materials: We investigated the potential contribution(s) of skeletal muscle sarcoplasmic reticulum Ca ATPase (SERCA) to muscle atrophy and weakness in asthmatic patients. Quadriceps muscle biopsies were taken from 58 to 72 years old male patients with mild and advanced asthma and the SERCA activity was analyzed in association with cellular redox environment and myonuclear domain (MND) size.

Key Findings: Maximal SERCA activity was reduced in skeletal muscles of mild and advanced asthmatics and was associated with reduced expression of SERCA2 protein and upregulation of sarcolipin, a SERCA inhibitory lipoprotein. We also found downregulation of Ca release protein calstabin and upregulation of Ca buffer, calsequestrin in skeletal muscles of asthmatic patients. The atrophic single muscle fibers had smaller cytoplasmic domains per myonucleus possibly indicating the reduced transcriptional reserves of individual myonuclei. Plasma periostin and CAF22 levels were significantly elevated in asthmatic patients and showed a strong correlation with hand-grip strength. These changes were accompanied by substantially elevated markers of global oxidative stress including lipid peroxidation and mitochondrial ROS production.

Conclusion: Taken together, our data suggest that muscle weakness and atrophy in asthma is in part driven by SERCA dysfunction and oxidative stress. The data propose SERCA dysfunction as a therapeutic intervention to address muscle decline in asthma.
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http://dx.doi.org/10.1016/j.lfs.2021.119296DOI Listing
May 2021

Signature molecular changes in the skeletal muscle of hindlimb unloaded mice.

Biochem Biophys Rep 2021 Mar 29;25:100930. Epub 2021 Jan 29.

Department of Basic Medical Sciences, College of Medicine, University of Sharjah, 27272, Sharjah, United Arab Emirates.

Hind-limb unloaded (HU) mouse is a well-recognized model of muscle atrophy; however, the molecular changes in the skeletal muscle during unloading are poorly characterized. We have used Raman spectroscopy to evaluate the structure and behavior of signature molecules involved in regulating muscle structural and functional health. The Raman spectroscopic analysis of gastrocnemius muscles was compared between 16-18 weeks old HU c57Bl/6J mice and ground-based controls. The spectra showed that the signals for asparagine and glutamine were reduced in HU mice, possibly indicating increased catabolism. The peaks for hydroxyproline and proline were split, pointing towards molecular breakdown and reduced tendon repair. We also report a consistently increased intensity in> 1300 cm range in the Raman spectra along with a shift towards higher frequencies in the HU mice, indicating activation of sarcoplasmic reticulum (SR) stress during HU.
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http://dx.doi.org/10.1016/j.bbrep.2021.100930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851774PMC
March 2021

Restoration of Sarcoplasmic Reticulum Ca ATPase (SERCA) Activity Prevents Age-Related Muscle Atrophy and Weakness in Mice.

Int J Mol Sci 2020 Dec 22;22(1). Epub 2020 Dec 22.

Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.

Sarcopenia has a significant negative impact on healthspan in the elderly and effective pharmacologic interventions remain elusive. We have previously demonstrated that sarcopenia is associated with reduced activity of the sarcoplasmic reticulum Ca ATPase (SERCA) pump. We asked whether restoring SERCA activity using pharmacologic activation in aging mice could mitigate the sarcopenia phenotype. We treated 16-month male C57BL/6J mice with vehicle or CDN1163, an allosteric SERCA activator, for 10 months. At 26 months, maximal SERCA activity was reduced 41% in gastrocnemius muscle in vehicle-treated mice but maintained in old CDN1163 treated mice. Reductions in gastrocnemius mass (9%) and in vitro specific force generation in extensor digitorum longus muscle (11%) in 26 versus 16-month-old wild-type mice were also reversed by CDN1163. CDN1163 administered by intra-peritoneal injection also prevented the increase in mitochondrial ROS production in gastrocnemius muscles of aged mice. Transcriptomic analysis revealed that these effects are at least in part mediated by enhanced cellular energetics by activation of PGC1-α, UCP1, HSF1, and APMK and increased regenerative capacity by suppression of MEF2C and p38 MAPK signaling. Together, these exciting findings are the first to support that pharmacological targeting of SERCA can be an effective therapy to counter age-related muscle dysfunction.
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http://dx.doi.org/10.3390/ijms22010037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792969PMC
December 2020

Growth and socio-economic status, influence on the age at menarche in school going girls.

J Adolesc 2021 Jan 9;86:40-53. Epub 2020 Dec 9.

Department of Finance and Economics, College of Business Administration, University of Sharjah, Sharjah, United Arab Emirates; Department of Social Sciences and Business, Roskilde University, Roskilde, Denmark.

Introduction: Onset age at menarche has been considered an important indicator of reproductive maturity in females and reflects the health status of the population. The purpose of this study was to determine the mean menarcheal age and to examine whether anthropometric and socio-economic status (SES) influences age at menarche in the girls from Punjab province of Pakistan.

Methods: In this population-based cross-sectional study, 10,050 school-going girls aged 8-16 years from 35 schools across 12 districts of Punjab were recruited. Menarcheal data was obtained by using a questionnaire, while the anthropometric data were obtained by the measurements of standing height, body weight, waist, and hip circumference. The anthropometric indices of pre- and post-menarcheal girls were compared. Student's t-test, ANOVA, and post-hoc Tukey's test was applied for comparison between two and multiple groups respectively, P < 0.05 was considered statistically significant.

Results: There was a normal distribution of age at menarche and mean was 12.4 years in the study population. The girls who reached menarche were found to be taller and heavier with higher BMIs, having a greater waist and hip circumference as compared to their pre-menarcheal peers. Waist-hip-ratio was less, and the waist-to-height ratio was higher in post-menarcheal as compared to pre-menarcheal girls. The girls belonging to low SES had delayed onset of menarche as compared to those belonging to middle/high SES.

Conclusion: The age at menarche was associated with SES and changes in various anthropometric measurements reflecting the growth status of girls.
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http://dx.doi.org/10.1016/j.adolescence.2020.12.001DOI Listing
January 2021

Circulating Biomarkers of Accelerated Sarcopenia in Respiratory Diseases.

Biology (Basel) 2020 Oct 3;9(10). Epub 2020 Oct 3.

Department of Cardiology, Al Qassimi Hospital, Sharjah 27272, UAE.

Skeletal muscle dysfunction is a critical finding in many respiratory diseases. However, a definitive biomarker to assess muscle decline in respiratory diseases is not known. We analyzed the association of plasma levels of glycoprotein Dickkopf-3 (Dkk-3), c-terminal agrin fragment-22 (CAF22) and microRNAs miR-21, miR-134a, miR-133 and miR-206 with hand-grip strength (HGS) and appendicular skeletal mass index (ASMI) in male, 54-73-year-old patients with chronic obstructive pulmonary diseases (COPD), asthma or pulmonary TB ( = 83-101/group). Patients with respiratory diseases showed a reduction in HGS and gait speed, while a reduction in ASMI was only found in patients with pulmonary TB. Among the sarcopenia indexes, HGS showed the strongest correlation with plasma CAF22, miR-21 and miR-206 levels while ASMI showed the strongest correlation with Dkk-3 and miR-133 in respiratory diseases. We found a modest-to-significant increase in the plasma markers of inflammation, oxidative stress and muscle damage, which had varying degrees of correlations with Dkk-3, CAF22 and selected micro RNAs (miRs) in respiratory diseases. Taken together, our data show that plasma levels of Dkk-3, CAF22 and selected miRs can be useful tools to assess accelerated sarcopenia phenotype in the elderly with respiratory diseases.
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http://dx.doi.org/10.3390/biology9100322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600620PMC
October 2020

Cancer cachexia in a mouse model of oxidative stress.

J Cachexia Sarcopenia Muscle 2020 12 12;11(6):1688-1704. Epub 2020 Sep 12.

Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.

Background: Cancer is associated with muscle atrophy (cancer cachexia) that is linked to up to 40% of cancer-related deaths. Oxidative stress is a critical player in the induction and progression of age-related loss of muscle mass and weakness (sarcopenia); however, the role of oxidative stress in cancer cachexia has not been defined. The purpose of this study was to examine if elevated oxidative stress exacerbates cancer cachexia.

Methods: Cu/Zn superoxide dismutase knockout (Sod1KO) mice were used as an established mouse model of elevated oxidative stress. Cancer cachexia was induced by injection of one million Lewis lung carcinoma (LLC) cells or phosphate-buffered saline (saline) into the hind flank of female wild-type mice or Sod1KO mice at approximately 4 months of age. The tumour developed for 3 weeks. Muscle mass, contractile function, neuromuscular junction (NMJ) fragmentation, metabolic proteins, mitochondrial function, and motor neuron function were measured in wild-type and Sod1KO saline and tumour-bearing mice. Data were analysed by two-way ANOVA with Tukey-Kramer post hoc test when significant F ratios were determined and α was set at 0.05. Unless otherwise noted, results in abstract are mean ±SEM.

Results: Muscle mass and cross-sectional area were significantly reduced, in tumour-bearing mice. Metabolic enzymes were dysregulated in Sod1KO mice and cancer exacerbated this phenotype. NMJ fragmentation was exacerbated in tumour-bearing Sod1KO mice. Myofibrillar protein degradation increased in tumour-bearing wild-type mice (wild-type saline, 0.00847 ± 0.00205; wildtype LLC, 0.0211 ± 0.00184) and tumour-bearing Sod1KO mice (Sod1KO saline, 0.0180 ± 0.00118; Sod1KO LLC, 0.0490 ± 0.00132). Muscle mitochondrial oxygen consumption was reduced in tumour-bearing mice compared with saline-injected wild-type mice. Mitochondrial protein degradation increased in tumour-bearing wild-type mice (wild-type saline, 0.0204 ± 0.00159; wild-type LLC, 0.167 ± 0.00157) and tumour-bearing Sod1KO mice (Sod1KO saline, 0.0231 ± 0.00108; Sod1 KO LLC, 0.0645 ± 0.000631). Sciatic nerve conduction velocity was decreased in tumour-bearing wild-type mice (wild-type saline, 38.2 ± 0.861; wild-type LLC, 28.8 ± 0.772). Three out of eleven of the tumour-bearing Sod1KO mice did not survive the 3-week period following tumour implantation.

Conclusions: Oxidative stress does not exacerbate cancer-induced muscle loss; however, cancer cachexia may accelerate NMJ disruption.
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http://dx.doi.org/10.1002/jcsm.12615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749559PMC
December 2020

Neuron-specific deletion of CuZnSOD leads to an advanced sarcopenic phenotype in older mice.

Aging Cell 2020 10 4;19(10):e13225. Epub 2020 Sep 4.

Aging & Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.

Age-associated loss of muscle mass and function (sarcopenia) has a profound effect on the quality of life in the elderly. Our previous studies show that CuZnSOD deletion in mice (Sod1 mice) recapitulates sarcopenia phenotypes, including elevated oxidative stress and accelerated muscle atrophy, weakness, and disruption of neuromuscular junctions (NMJs). To determine whether deletion of Sod1 initiated in neurons in adult mice is sufficient to induce muscle atrophy, we treated young (2- to 4-month-old) Sod1flox/SlickHCre mice with tamoxifen to generate i-mn-Sod1KO mice. CuZnSOD protein was 40-50% lower in neuronal tissue in i-mn-Sod1KO mice. Motor neuron number in ventral spinal cord was reduced 28% at 10 months and more than 50% in 18- to 22-month-old i-mn-Sod1KO mice. By 24 months, 22% of NMJs in i-mn-Sod1KO mice displayed a complete lack of innervation and deficits in specific force that are partially reversed by direct muscle stimulation, supporting the loss of NMJ structure and function. Muscle mass was significantly reduced by 16 months of age and further decreased at 24 months of age. Overall, our findings show that neuronal-specific deletion of CuZnSOD is sufficient to cause motor neuron loss in young mice, but that NMJ disruption, muscle atrophy, and weakness are not evident until past middle age. These results suggest that loss of innervation is critical but may not be sufficient until the muscle reaches a threshold beyond which it cannot compensate for neuronal loss or rescue additional fibers past the maximum size of the motor unit.
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http://dx.doi.org/10.1111/acel.13225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576239PMC
October 2020

Plasma CAF22 Levels as a Useful Predictor of Muscle Health in Patients with Chronic Obstructive Pulmonary Disease.

Biology (Basel) 2020 Jul 15;9(7). Epub 2020 Jul 15.

Department of Biochemistry, Gomal Medical College, Dera Ismail Khan 29050, Pakistan.

Skeletal muscle dysfunction and reduced physical capacity are characteristic features of chronic obstructive pulmonary disease (COPD). However, the search for a reliable biomarker to assess muscle health in CODP remains elusive. We analyzed the course of hand-grip strength (HGS) and appendicular skeletal mass index (ASMI) in COPD in relation to spirometry decline and plasma extracellular heat shock protein-72 (eHSP72) and c-terminal fragment of agrin-22 (CAF22) levels. We evaluated male, 62-73 years old patients of COPD ( = 265) and healthy controls ( = 252) at baseline and after 12 and 24 months for plasma biomarkers, spirometry and HGS measurements. HGS declined significantly over time and plasma CAF22, but not eHSP72 levels, had a significant negative association with HGS and ASMI in COPD. Plasma CAF22 also had an association with walking speed and daily steps count in advanced COPD. Lower ASMI was associated with reduced HGS at all time-point. Narrow age-span of the study cohort and exclusion of lower-limb muscles from the analysis are limitations of this study. Taken together, we report that the plasma CAF22 may be a useful tool to assess muscle weakness and atrophy in COPD patients.
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http://dx.doi.org/10.3390/biology9070166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408122PMC
July 2020

Anthropometric measurements of school-going-girls of the Punjab, Pakistan.

BMC Pediatr 2020 05 16;20(1):223. Epub 2020 May 16.

Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, UAE.

Background: Child's growth has been considered an important indicator to evaluate health trends in a population and to devise strategies accordingly. The purpose of the present study was to determine most commonly occurring weight abnormalities among school-going girls from Punjab and to compare with international growth references devised by World Health Organization (WHO) and Centre for Disease Control and Prevention (CDC).

Methods: In this cross-sectional study a sample of 10,050 child and adolescent girls from 12 districts, 35 public/private sector schools, located in rural, semi-urban and urban areas of northern, central and southern Punjab were included. Parameters were measured according to standardised techniques and centile curves obtained by Lambda, Mu, Sigma (LMS) method.

Results: The results showed an increase in weight, height and BMI of the Punjabi girls until 15 years. When compared with international growth references, weight and BMI in our population were significantly lowered; however, height was lower during 12-16 years of age and the differences observed were more pronounced with CDC as compared to WHO. When 3rd, 50th and 90th percentiles of weight, height and BMI in our population were compared with international standards, the values were lower in our paediatric population.

Conclusion: The Punjabi schoolgirls significantly differed from CDC and WHO references, and this difference should be taken into consideration for evaluation of growth abnormalities in our paediatric population. However, in the absence of national reference data, WHO standards have been considered more appropriate for comparison.
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http://dx.doi.org/10.1186/s12887-020-02135-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229613PMC
May 2020

Circulating Biomarkers of Handgrip Strength and Lung Function in Chronic Obstructive Pulmonary Disease.

Int J Chron Obstruct Pulmon Dis 2020 11;15:311-321. Epub 2020 Feb 11.

Department of Biochemistry, Gomal Medical College, Gomal University, Dera Ismail Khan, Pakistan.

Purpose: COPD is a multisystem disease and there is a need for clinical serum markers that can assess the decline in lung and muscle function in COPD. The goal of this study was to evaluate the potential association of serum club-cell protein 16 (CC16), α-1 acid glycoprotein (AGP) and total sialic acid (TSA) with spirometry, hand-grip strength and quality of life to assess important disease outcomes.

Methods: This is a population-based cross-sectional study and data were collected from the patients at teaching hospitals of Gomal University and the University of Health Sciences in Pakistan. The study population included 1582 participants (Non-COPD; N = 788, COPD; N = 845) >55 years of age from both sexes, with data from structural interviews, clinical examinations, laboratory investigations, spirometry and hand-grip strength measurements.

Results: Serum TSA and CC16 were significant predictors of FEV% (p < 0.05) and hand-grip strength in advanced stages of COPD (p < 0.05 each) in both sexes. Men had higher absolute and adjusted hand-grip strength than women in all groups (p < 0.05). Hand-grip strength was significantly associated with FEV% in both genders (p < 0.05) with stronger effect in women (r = 0.075). Serum HDL-C was an independent predictor of hand-grip strength and FEV% (p < 0.05) in both genders. Participants with extreme problem on EQ-5D parameters had more severe COPD and reduced hand-grip strength (all p values < 0.05).

Conclusion: Taken together, these studies show that the serum expressions of TSA and CC16 have correlations with spirometry and muscle decline in COPD. Further studies should be conducted to establish their efficacy in monitoring disease progression in COPD.
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http://dx.doi.org/10.2147/COPD.S225765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7023869PMC
February 2021

Muscle unloading: A comparison between spaceflight and ground-based models.

Acta Physiol (Oxf) 2020 03 30;228(3):e13431. Epub 2019 Dec 30.

Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, UAE.

Prolonged unloading of skeletal muscle, a common outcome of events such as spaceflight, bed rest and hindlimb unloading, can result in extensive metabolic, structural and functional changes in muscle fibres. With advancement in investigations of cellular and molecular mechanisms, understanding of disuse muscle atrophy has significantly increased. However, substantial gaps exist in our understanding of the processes dictating muscle plasticity during unloading, which prevent us from developing effective interventions to combat muscle loss. This review aims to update the status of knowledge and underlying mechanisms leading to cellular and molecular changes in skeletal muscle during unloading. We have also discussed advances in the understanding of contractile dysfunction during spaceflights and in ground-based models of muscle unloading. Additionally, we have elaborated on potential therapeutic interventions that show promising results in boosting muscle mass and strength during mechanical unloading. Finally, we have identified key gaps in our knowledge as well as possible research direction for the future.
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http://dx.doi.org/10.1111/apha.13431DOI Listing
March 2020

Restoration of SERCA ATPase prevents oxidative stress-related muscle atrophy and weakness.

Redox Biol 2019 01 27;20:68-74. Epub 2018 Sep 27.

Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; Oklahoma City VA Medical Center, Oklahoma City, OK 73104, USA. Electronic address:

Molecular targets to reduce muscle weakness and atrophy due to oxidative stress have been elusive. Here we show that activation of Sarcoplasmic Reticulum (SR) Ca ATPase (SERCA) with CDN1163, a novel small molecule allosteric SERCA activator, ameliorates the muscle impairment in the CuZnSOD deficient (Sod1) mouse model of oxidative stress. Sod1 mice are characterized by reduced SERCA activity, muscle weakness and atrophy, increased oxidative stress and mitochondrial dysfunction. Seven weeks of CDN1163 treatment completely restored SERCA activity and reversed the 23% reduction in gastrocnemius mass and 22% reduction in specific force in untreated Sod1 versus wild type mice. These changes were accompanied by restoration of autophagy protein markers to the levels found in wild-type mice. CDN1163 also reversed the increase in mitochondrial ROS generation and oxidative damage in muscle tissue from Sod1 mice. Taken together our findings suggest that the pharmacological restoration of SERCA is a promising therapeutic approach to counter oxidative stress-associated muscle impairment.
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http://dx.doi.org/10.1016/j.redox.2018.09.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174848PMC
January 2019

Oxidative stress-induced dysregulation of excitation-contraction coupling contributes to muscle weakness.

J Cachexia Sarcopenia Muscle 2018 10 2;9(5):1003-1017. Epub 2018 Aug 2.

Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.

Background: We have previously shown that the deletion of the superoxide scavenger, CuZn superoxide dismutase, in mice (Sod1 mice) results in increased oxidative stress and an accelerated loss of skeletal muscle mass and force that mirror the changes seen in old control mice. The goal of this study is to define the effect of oxidative stress and ageing on muscle weakness and the Excitation Contraction (EC) coupling machinery in age-matched adult (8-10 months) wild-type (WT) and Sod1 mice in comparison with old (25-28 months) WT mice.

Methods: In vitro contractile assays were used to measure muscle contractile parameters. The activity of the sarcoplasmic reticulum Ca ATPase (SERCA) pump was measured using an NADH-linked enzyme assay. Immunoblotting and immunofluorescence techniques were used to measure protein expression, and real-time reverse transcription PCR was used to measure gene expression.

Results: The specific force generated by the extensor digitorum longus muscle was reduced in the Sod1 and old WT mice compared with young WT mice along with significant prolongation of time to peak force, increased half relaxation time, and disruption of intracellular calcium handling. The maximal activity of the SERCA calcium uptake pump was significantly reduced in gastrocnemius muscle from both old WT (≈14%) and adult Sod1 (≈33%) mice compared with young WT mice along with increased expression of sarcolipin, a known inhibitor of SERCA activity. Protein levels of the voltage sensor and calcium uptake channel proteins dihydropyridine receptor α1 and SERCA2 were significantly elevated (≈45% and ≈57%, respectively), while the ratio of calstabin, a channel stabilizing protein, to ryanodine receptor was significantly reduced (≈21%) in Sod1 mice compared with young WT mice. The changes in calcium handling were accompanied by substantially elevated levels of global protein carbonylation and lipid peroxidation.

Conclusions: Our data suggest that the muscle weakness in Sod1 and old WT mice is in part driven by reactive oxygen species-mediated EC uncoupling and supports a role for reduced SERCA pump activity in compromised muscle function. The novel quantitative mechanistic data provided here can lead to potential therapeutic interventions of SERCA dysfunction for sarcopenia and muscle diseases.
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http://dx.doi.org/10.1002/jcsm.12339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6204588PMC
October 2018

A fish oil diet induces mitochondrial uncoupling and mitochondrial unfolded protein response in epididymal white adipose tissue of mice.

Free Radic Biol Med 2017 07 26;108:704-714. Epub 2017 Apr 26.

Department of Geriatric Medicine and the Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA. Electronic address:

White adipose tissue (WAT) mitochondrial dysfunction is linked to the pathogenesis of obesity driven insulin resistance. Dietary conditions that alter fat mass are known to affect white adipocyte mitochondrial function, however, the impact of high calorie diets on white adipocyte mitochondria is not fully understood. The aim of this study is to assess the effect of a diet rich in saturated or polyunsaturated fat on mitochondrial unfolded protein response (UPR), a retrograde signaling response that maintains mitochondrial homeostasis, in epididymal WAT (eWAT). Mice were fed a low fat diet (LFD), saturated fat diet (SFD) or fish oil (unsaturated fat diet, UFD) and assessed changes in eWAT mitochondria. Compared to mice fed a LFD, SFD-fed mice have reduced mitochondrial biogenesis markers, mitochondrial fatty acid oxidation enzymes and TCA cycle enzymes, suggesting an impaired mitochondrial function that could contribute to increased fat mass. In contrast, isocaloric UFD-fed mice have increased expression of mitochondrial uncoupling protein 1 (UCP1) and peroxisomal fatty acid oxidation enzymes suggesting that elevated mitochondrial uncoupling and peroxisomal fatty acid oxidation could contribute to the reduction in fat mass. Interestingly, expression of UPR-associated proteins caseinolytic peptidase (ClpP) and heat shock protein 60 (Hsp60) are induced by UFD, whereas SFD reduced the expression of ClpP. Based on our data, we propose that induction of UPR helps to preserve a functional mitochondria and efficient utilization of fat by UFD whereas a dampened UPR response might impair mitochondrial function and promote fat accumulation by SFD. Thus, our findings suggest a potential role of UPR in mediating the beneficial effects of fish oil.
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http://dx.doi.org/10.1016/j.freeradbiomed.2017.04.028DOI Listing
July 2017

Enhanced GLUT4-Dependent Glucose Transport Relieves Nutrient Stress in Obese Mice Through Changes in Lipid and Amino Acid Metabolism.

Diabetes 2016 Dec 27;65(12):3585-3597. Epub 2016 Sep 27.

Department of Biochemistry & Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK

Impaired GLUT4-dependent glucose uptake is a contributing factor in the development of whole-body insulin resistance in obese patients and obese animal models. Previously, we demonstrated that transgenic mice engineered to express the human GLUT4 gene under the control of the human GLUT4 promoter (i.e., transgenic [TG] mice) are resistant to obesity-induced insulin resistance. A likely mechanism underlying increased insulin sensitivity is increased glucose uptake in skeletal muscle. The purpose of this study was to investigate the broader metabolic consequences of enhanced glucose uptake into muscle. We observed that the expression of several nuclear and mitochondrially encoded mitochondrial enzymes was decreased in TG mice but that mitochondrial number, size, and fatty acid respiration rates were unchanged. Interestingly, both pyruvate and glutamate respiration rates were decreased in TG mice. Metabolomics analyses of skeletal muscle samples revealed that increased GLUT4 transgene expression was associated with decreased levels of some tricarboxylic acid intermediates and amino acids, whereas the levels of several glucogenic amino acids were elevated. Furthermore, fasting acyl carnitines in obese TG mice were decreased, indicating that increased GLUT4-dependent glucose flux decreases nutrient stress by altering lipid and amino acid metabolism in skeletal muscle.
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http://dx.doi.org/10.2337/db16-0709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127250PMC
December 2016

Muscle fiber type diversification during exercise and regeneration.

Free Radic Biol Med 2016 09 29;98:56-67. Epub 2016 Mar 29.

Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA. Electronic address:

The plasticity of skeletal muscle can be traced down to extensive metabolic, structural and molecular remodeling at the single fiber level. Skeletal muscle is comprised of different fiber types that are the basis of muscle plasticity in response to various functional demands. Resistance and endurance exercises are two external stimuli that differ in their duration and intensity of contraction and elicit markedly different responses in muscles adaptation. Further, eccentric contractions that are associated with exercise-induced injuries, elicit varied muscle adaptation and regenerative responses. Most adaptive changes are fiber type-specific and are highly influenced by diverse structural, metabolic and functional characteristics of individual fiber types. Regulation of signaling pathways by reactive oxygen species (ROS) and oxidative stress also plays an important role in muscle fiber adaptation during exercise. This review focuses on cellular and molecular responses that regulate the adaptation of skeletal muscle to exercise and exercise-related injuries.
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http://dx.doi.org/10.1016/j.freeradbiomed.2016.03.025DOI Listing
September 2016

Down-regulation of the mitochondrial matrix peptidase ClpP in muscle cells causes mitochondrial dysfunction and decreases cell proliferation.

Free Radic Biol Med 2016 Feb 23;91:281-92. Epub 2015 Dec 23.

Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; Oklahoma City VA Medical Center, Oklahoma City, OK 73104, USA.

The caseinolytic peptidase P (ClpP) is the endopeptidase component of the mitochondrial matrix ATP-dependent ClpXP protease. ClpP degrades unfolded proteins to maintain mitochondrial protein homeostasis and is involved in the initiation of the mitochondrial unfolded protein response (UPR(mt)). Outside of an integral role in the UPR(mt), the cellular function of ClpP is not well characterized in mammalian cells. To investigate the role of ClpP in mitochondrial function, we generated C2C12 muscle cells that are deficient in ClpP using siRNA or stable knockdown using lentiviral transduction. Reduction of ClpP levels by ~70% in C2C12 muscle cells resulted in a number of mitochondrial alterations including reduced mitochondrial respiration and reduced oxygen consumption rate in response to electron transport chain (ETC) complex I and II substrates. The reduction in ClpP altered mitochondrial morphology, changed the expression level of mitochondrial fission protein Drp1 and blunted UPR(mt) induction. In addition, ClpP deficient cells showed increased generation of reactive oxygen species (ROS) and decreased membrane potential. At the cellular level, reduction of ClpP impaired myoblast differentiation, cell proliferation and elevated phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α) suggesting an inhibition of translation. Our study is the first to define the effects of ClpP deficiency on mitochondrial function in muscle cells in vitro. In addition, we have uncovered novel effects of ClpP on mitochondrial morphology, cell proliferation and protein translation pathways in muscle cells.
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http://dx.doi.org/10.1016/j.freeradbiomed.2015.12.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5584630PMC
February 2016

The histone deacetylase inhibitor butyrate improves metabolism and reduces muscle atrophy during aging.

Aging Cell 2015 Dec 20;14(6):957-70. Epub 2015 Aug 20.

Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.

Sarcopenia, the loss of skeletal muscle mass and function during aging, is a major contributor to disability and frailty in the elderly. Previous studies found a protective effect of reduced histone deacetylase activity in models of neurogenic muscle atrophy. Because loss of muscle mass during aging is associated with loss of motor neuron innervation, we investigated the potential for the histone deacetylase (HDAC) inhibitor butyrate to modulate age-related muscle loss. Consistent with previous studies, we found significant loss of hindlimb muscle mass in 26-month-old C57Bl/6 female mice fed a control diet. Butyrate treatment starting at 16 months of age wholly or partially protected against muscle atrophy in hindlimb muscles. Butyrate increased muscle fiber cross-sectional area and prevented intramuscular fat accumulation in the old mice. In addition to the protective effect on muscle mass, butyrate reduced fat mass and improved glucose metabolism in 26-month-old mice as determined by a glucose tolerance test. Furthermore, butyrate increased markers of mitochondrial biogenesis in skeletal muscle and whole-body oxygen consumption without affecting activity. The increase in mass in butyrate-treated mice was not due to reduced ubiquitin-mediated proteasomal degradation. However, butyrate reduced markers of oxidative stress and apoptosis and altered antioxidant enzyme activity. Our data is the first to show a beneficial effect of butyrate on muscle mass during aging and suggests HDACs contribute to age-related muscle atrophy and may be effective targets for intervention in sarcopenia and age-related metabolic disease.
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http://dx.doi.org/10.1111/acel.12387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4693467PMC
December 2015

Neuron specific reduction in CuZnSOD is not sufficient to initiate a full sarcopenia phenotype.

Redox Biol 2015 Aug 15;5:140-148. Epub 2015 Apr 15.

Free Radical Biology and Aging Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; Oklahoma VA Medical Center, Oklahoma City, OK 73104, USA. Electronic address:

Our previous studies showed that adult (8 month) mice lacking CuZn-superoxide dismutase (CuZnSOD, Sod1KO mice) have neuromuscular changes resulting in dramatic accelerated muscle atrophy and weakness that mimics age-related sarcopenia. We have further shown that loss of CuZnSOD targeted to skeletal muscle alone results in only mild weakness and no muscle atrophy. In this study, we targeted deletion of CuZnSOD specifically to neurons (nSod1KO mice) and determined the effect on muscle mass and weakness. The nSod1KO mice show a significant loss of CuZnSOD activity and protein level in brain and spinal cord but not in muscle tissue. The masses of the gastrocnemius, tibialis anterior and extensor digitorum longus (EDL) muscles were not reduced in nSod1KO compared to wild type mice, even at 20 months of age, although the quadriceps and soleus muscles showed small but statistically significant reductions in mass in the nSod1KO mice. Maximum isometric specific force was reduced by 8-10% in the gastrocnemius and EDL muscle of nSod1KO mice, while soleus was not affected. Muscle mitochondrial ROS generation and oxidative stress measured by levels of reactive oxygen/nitrogen species (RONS) regulatory enzymes, protein nitration and F2-isoprostane levels were not increased in muscle from the nSod1KO mice. Although we did not find evidence of denervation in the nSod1KO mice, neuromuscular junction morphology was altered and the expression of genes associated with denervation acetylcholine receptor subunit alpha (AChRα), the transcription factor, Runx1 and GADD45α) was increased, supporting a role for neuronal loss of CuZnSOD initiating alterations at the neuromuscular junction. These results and our previous studies support the concept that CuZnSOD deficits in either the motor neuron or muscle alone are not sufficient to initiate a full sarcopenic phenotype and that deficits in both tissues are required to recapitulate the loss of muscle observed in Sod1KO mice.
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http://dx.doi.org/10.1016/j.redox.2015.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5022075PMC
August 2015

Quantitative and qualitative adaptations of muscle fibers to glucocorticoids.

Muscle Nerve 2015 Oct 30;52(4):631-9. Epub 2015 Jun 30.

Department of Molecular Medicine, University of Pavia, Pavia, Italy.

Introduction: The aim of this study was to understand the effects of short-term glucocorticoid administration in healthy subjects.

Methods: Five healthy men received dexamethasone (8 mg/day) for 7 days. Vastus lateralis muscle biopsy and knee extension torque measurement were performed before and after administration. A large number of individual muscle fibers were dissected from the biopsy samples (pre-administration: n = 165, post-administration: n = 177).

Results: Maximal knee extension torque increased after administration (∼ 13%), whereas both type 1 and type 2A fibers had decreased cross-sectional area (type 1: ∼ 11%, type 2A: ∼ 17%), myosin loss (type 1: ∼ 18%, type 2A: ∼ 32%), and loss of specific force (type 1: ∼ 24%, type 2A: ∼ 33%), which were preferential for fast fibers.

Conclusion: Short-term dexamethasone administration in healthy subjects elicits quantitative and qualitative adaptations of muscle fibers that precede (and may predict) the clinical appearance of myopathy in glucocorticoid-treated subjects.
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http://dx.doi.org/10.1002/mus.24572DOI Listing
October 2015

Hormone replacement therapy improves contractile function and myonuclear organization of single muscle fibres from postmenopausal monozygotic female twin pairs.

J Physiol 2013 May 4;591(9):2333-44. Epub 2013 Mar 4.

Department of Neuroscience, Clinical Neurophysiology, Uppsala University, Sweden.

Ageing is associated with a decline in muscle mass and strength leading to increased physical dependency in old age. Postmenopausal women experience a greater decline than men of similar age in parallel with the decrease in female sex steroid hormone production. We recruited six monozygous female twin pairs (55-59 years old) where only one twin pair was on hormone replacement therapy (HRT use = 7.8 ± 4.3 years) to investigate the association of HRT with the cytoplasmic volume supported by individual myonuclei (myonuclear domain (MND) size,) together with specific force at the single fibre level. HRT use was associated with a significantly smaller (∼27%; P < 0.05) mean MND size in muscle fibres expressing the type I but not the IIa myosin heavy chain (MyHC) isoform. In comparison to non-users, higher specific force was recorded in HRT users both in muscle fibres expressing type I (∼27%; P < 0.05) and type IIa (∼23%; P < 0.05) MyHC isoforms. These differences were fibre-type dependent, i.e. the higher specific force in fast-twitch muscle fibres was primarily caused by higher force per cross-bridge while slow-twitch fibres relied on both a higher number and force per cross-bridge. HRT use had no effect on fibre cross-sectional area (CSA), velocity of unloaded shortening (V0) and relative proportion of MyHC isoforms. In conclusion, HRT appears to have significant positive effects on both regulation of muscle contraction and myonuclei organization in postmenopausal women.
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http://dx.doi.org/10.1113/jphysiol.2012.250092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3650698PMC
May 2013

Loss of muscle strength during sepsis is in part regulated by glucocorticoids and is associated with reduced muscle fiber stiffness.

Am J Physiol Regul Integr Comp Physiol 2012 Nov 26;303(10):R1090-9. Epub 2012 Sep 26.

Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

Sepsis is associated with impaired muscle function but the role of glucocorticoids in sepsis-induced muscle weakness is not known. We tested the role of glucocorticoids in sepsis-induced muscle weakness by treating septic rats with the glucocorticoid receptor antagonist RU38486. In addition, normal rats were treated with dexamethasone to further examine the role of glucocorticoids in the regulation of muscle strength. Sepsis was induced in rats by cecal ligation and puncture, and muscle force generation (peak twitch and tetanic tension) was determined in lower extremity muscles. In other experiments, absolute and specific force as well as stiffness (reflecting the function of actomyosin cross bridges) were determined in isolated skinned muscle fibers from control and septic rats. Sepsis and treatment with dexamethasone resulted in reduced maximal twitch and tetanic force in intact isolated extensor digitorum longus muscles. The absolute and specific maximal force in isolated muscle fibers was reduced during sepsis together with decreased fiber stiffness. These effects of sepsis were blunted (but not abolished) by RU38486. The results suggest that muscle weakness during sepsis is at least in part regulated by glucocorticoids and reflects loss of contractility at the cellular (individual muscle fiber) level. In addition, the results suggest that reduced function of the cross bridges between actin and myosin (documented as reduced muscle fiber stiffness) may be involved in sepsis-induced muscle weakness. An increased understanding of mechanisms involved in loss of muscle strength will be important for the development of new treatment strategies in patients with this debilitating consequence of sepsis.
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http://dx.doi.org/10.1152/ajpregu.00636.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3517670PMC
November 2012

Is functional hypertrophy and specific force coupled with the addition of myonuclei at the single muscle fiber level?

FASEB J 2012 Mar 28;26(3):1077-85. Epub 2011 Nov 28.

Department of Neuroscience, Uppsala University, SE-751 85 Uppsala, Sweden.

Muscle force is typically proportional to muscle size, resulting in constant force normalized to muscle fiber cross-sectional area (specific force). Mice overexpressing insulin-like growth factor-1 (IGF-1) exhibit a proportional gain in muscle force and size, but not the myostatin-deficient mice. In an attempt to explore the role of the cytoplasmic volume supported by individual myonuclei [myonuclear domain (MND) size] on functional capacity of skeletal muscle, we have investigated specific force in relation to MND and the content of the molecular motor protein, myosin, at the single muscle fiber level from myostatin-knockout (Mstn(-/-)) and IGF-1-overexpressing (mIgf1(+/+)) mice. We hypothesize that the addition of extra myonuclei is a prerequisite for maintenance of specific force during muscle hypertrophy. A novel algorithm was used to measure individual MNDs in 3 dimensions along the length of single muscle fibers from the fast-twitch extensor digitorum longus and the slow-twitch soleus muscle. A significant effect of the size of individual MNDs in hypertrophic muscle fibers on both specific force and myosin content was observed. This effect was muscle cell type specific and suggested there is a critical volume individual myonuclei can support efficiently. The large MNDs found in fast muscles of Mstn(-/-) mice were correlated with the decrement in specific force and myosin content in Mstn(-/-) muscles. Thus, myostatin inhibition may not be able to maintain the appropriate MND for optimal function.
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http://dx.doi.org/10.1096/fj.11-192195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050333PMC
March 2012

Preferential skeletal muscle myosin loss in response to mechanical silencing in a novel rat intensive care unit model: underlying mechanisms.

J Physiol 2011 Apr 14;589(Pt 8):2007-26. Epub 2011 Feb 14.

Department of Neuroscience, Clinical Neurophysiology, Uppsala University, Uppsala, Sweden.

The muscle wasting and impaired muscle function in critically ill intensive care unit (ICU) patients delay recovery from the primary disease, and have debilitating consequences that can persist for years after hospital discharge. It is likely that, in addition to pernicious effects of the primary disease, the basic life support procedures of long-term ICU treatment contribute directly to the progressive impairment of muscle function. This study aims at improving our understanding of the mechanisms underlying muscle wasting in ICU patients by using a unique experimental rat ICU model where animals are mechanically ventilated, sedated and pharmacologically paralysed for duration varying between 6 h and 14 days. Results show that the ICU intervention induces a phenotype resembling the severe muscle wasting and paralysis associated with the acute quadriplegic myopathy (AQM) observed in ICU patients, i.e. a preferential loss of myosin, transcriptional down-regulation of myosin synthesis, muscle atrophy and a dramatic decrease in muscle fibre force generation capacity. Detailed analyses of protein degradation pathways show that the ubiquitin proteasome pathway is highly involved in this process. A sequential change in localisation of muscle-specific RING finger proteins 1/2 (MuRF1/2) observed during the experimental period is suggested to play an instrumental role in both transcriptional regulation and protein degradation. We propose that, for those critically ill patients who develop AQM, complete mechanical silencing, due to pharmacological paralysis or sedation, is a critical factor underlying the preferential loss of the molecular motor protein myosin that leads to impaired muscle function or persisting paralysis.
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http://dx.doi.org/10.1113/jphysiol.2010.202044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3090600PMC
April 2011

Effects of aging and gender on the spatial organization of nuclei in single human skeletal muscle cells.

Aging Cell 2010 Oct 21;9(5):685-97. Epub 2010 Jul 21.

Department of Clinical Neurophysiology, Uppsala University, Sweden.

The skeletal muscle fibre is a syncitium where each myonucleus regulates the gene products in a finite volume of the cytoplasm, i.e., the myonuclear domain (MND). We analysed aging- and gender-related effects on myonuclei organization and the MND size in single muscle fibres from six young (21-31 years) and nine old men (72-96 years), and from six young (24-32 years) and nine old women (65-96 years), using a novel image analysis algorithm applied to confocal images. Muscle fibres were classified according to myosin heavy chain (MyHC) isoform expression. Our image analysis algorithm was effective in determining the spatial organization of myonuclei and the distribution of individual MNDs along the single fibre segments. Significant linear relations were observed between MND size and fibre size, irrespective age, gender and MyHC isoform expression. The spatial organization of individual myonuclei, calculated as the distribution of nearest neighbour distances in 3D, and MND size were affected in old age, but changes were dependent on MyHC isoform expression. In type I muscle fibres, average NN-values were lower and showed an increased variability in old age, reflecting an aggregation of myonuclei in old age. Average MND size did not change in old age, but there was an increased MND size variability. In type IIa fibres, average NN-values and MND sizes were lower in old age, reflecting the smaller size of these muscle fibres in old age. It is suggested that these changes have a significant impact on protein synthesis and degradation during the aging process.
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http://dx.doi.org/10.1111/j.1474-9726.2010.00594.xDOI Listing
October 2010

Myonuclear domain size and myosin isoform expression in muscle fibres from mammals representing a 100,000-fold difference in body size.

Exp Physiol 2009 Jan 26;94(1):117-29. Epub 2008 Sep 26.

Department of Neurosciences, Uppsala University, Uppsala, Sweden.

This comparative study of myonuclear domain (MND) size in mammalian species representing a 100,000-fold difference in body mass, ranging from 25 g to 2500 kg, was undertaken to improve our understanding of myonuclear organization in skeletal muscle fibres. Myonuclear domain size was calculated from three-dimensional reconstructions in a total of 235 single muscle fibre segments at a fixed sarcomere length. Irrespective of species, the largest MND size was observed in muscle fibres expressing fast myosin heavy chain (MyHC) isoforms, but in the two smallest mammalian species studied (mouse and rat), MND size was not larger in the fast-twitch fibres expressing the IIA MyHC isofom than in the slow-twitch type I fibres. In the larger mammals, the type I fibres always had the smallest average MND size, but contrary to mouse and rat muscles, type IIA fibres had lower mitochondrial enzyme activities than type I fibres. Myonuclear domain size was highly dependent on body mass in the two muscle fibre types expressed in all species, i.e. types I and IIA. Myonuclear domain size increased in muscle fibres expressing both the beta/slow (type I; r = 0.84, P < 0.001) and the fast IIA MyHC isoform (r = 0.90; P < 0.001). Thus, MND size scales with body size and is highly dependent on muscle fibre type, independent of species. However, myosin isoform expression is not the sole protein determining MND size, and other protein systems, such as mitochondrial proteins, may be equally or more important determinants of MND size.
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http://dx.doi.org/10.1113/expphysiol.2008.043877DOI Listing
January 2009