Rs1769793 variant reduces EGLN1 expression in skeletal muscle and hippocampus and contributes to high aerobic capacity in hypoxia.
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ABSTRACT:
SUBMITTER: Liu G
PROVIDER: S-EPMC7703601 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Physical exercise has profound effects on quality of life and susceptibility to chronic disease; however, the regulation of skeletal muscle function at the molecular level after exercise remains unclear. We tested the hypothesis that the benefits of exercise on muscle function are linked partly to microtraumatic events that result in accumulation of circulating heme. Effective metabolism of heme is controlled by Heme Oxygenase-1 (HO-1, Hmox1), and we find that mouse skeletal muscle-specific HO-1 deletion (Tam-Cre-HSA-Hmox1fl/fl) shifts the proportion of muscle fibers from type IIA to type IIB concomitant with a disruption in mitochondrial content and function. In addition to a significant impairment in running performance and response to exercise training, Tam-Cre-HSA-Hmox1fl/fl mice show remarkable muscle atrophy compared to Hmox1fl/fl controls. Collectively, these data define a role for heme and HO-1 as central regulators in the physiologic response of skeletal muscle to exercise.
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Project description:Exercise capacity is a strong predictor of all-cause mortality. Skeletal muscle mitochondrial respiratory capacity, its biggest contributor, adapts robustly to changes in energy demands induced by contractile activity. While transcriptional regulation of mitochondrial enzymes has been extensively studied, there is limited information on how mitochondrial membrane lipids are regulated. Here, we show that exercise training or muscle disuse alters mitochondrial membrane phospholipids including phosphatidylethanolamine (PE). Addition of PE promoted, whereas removal of PE diminished, mitochondrial respiratory capacity. Unexpectedly, skeletal muscle-specific inhibition of mitochondria-autonomous synthesis of PE caused respiratory failure because of metabolic insults in the diaphragm muscle. While mitochondrial PE deficiency coincided with increased oxidative stress, neutralization of the latter did not rescue lethality. These findings highlight the previously underappreciated role of mitochondrial membrane phospholipids in dynamically controlling skeletal muscle energetics and function.
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Project description:RATIONALE:Exercise capacity is a physiological characteristic associated with protection from both cardiovascular and all-cause mortality. p53 regulates mitochondrial function and its deletion markedly diminishes exercise capacity, but the underlying genetic mechanism orchestrating this is unclear. Understanding the biology of how p53 improves exercise capacity may provide useful insights for improving both cardiovascular as well as general health. OBJECTIVE:The purpose of this study was to understand the genetic mechanism by which p53 regulates aerobic exercise capacity. METHODS AND RESULTS:Using a variety of physiological, metabolic, and molecular techniques, we further characterized maximum exercise capacity and the effects of training, measured various nonmitochondrial and mitochondrial determinants of exercise capacity, and examined putative regulators of mitochondrial biogenesis. As p53 did not affect baseline cardiac function or inotropic reserve, we focused on the involvement of skeletal muscle and now report a wider role for p53 in modulating skeletal muscle mitochondrial function. p53 interacts with Mitochondrial Transcription Factor A (TFAM), a nuclear-encoded gene important for mitochondrial DNA (mtDNA) transcription and maintenance, and regulates mtDNA content. The increased mtDNA in p53(+/+) compared to p53(-/-) mice was more marked in aerobic versus glycolytic skeletal muscle groups with no significant changes in cardiac tissue. These in vivo observations were further supported by in vitro studies showing overexpression of p53 in mouse myoblasts increases both TFAM and mtDNA levels whereas depletion of TFAM by shRNA decreases mtDNA content. CONCLUSIONS:Our current findings indicate that p53 promotes aerobic metabolism and exercise capacity by using different mitochondrial genes and mechanisms in a tissue-specific manner.
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Project description:Contemporary tissue engineered skeletal muscle models display a high degree of physiological accuracy compared with native tissue, and therefore may be excellent platforms to understand how various pathologies affect skeletal muscle. Chronic obstructive pulmonary disease (COPD) is a lung disease which causes tissue hypoxia and is characterized by muscle fiber atrophy and impaired muscle function. In the present study we exposed engineered skeletal muscle to varying levels of oxygen (O2 ; 21-1%) for 24?h in order to see if a COPD like muscle phenotype could be recreated in vitro, and if so, at what degree of hypoxia this occurred. Maximal contractile force was attenuated in hypoxia compared to 21% O2 ; with culture at 5% and 1% O2 causing the most pronounced effects with 62% and 56% decrements in force, respectively. Furthermore at these levels of O2 , myotubes within the engineered muscles displayed significant atrophy which was not seen at higher O2 levels. At the molecular level we observed increases in mRNA expression of MuRF-1 only at 1% O2 whereas MAFbx expression was elevated at 10%, 5%, and 1% O2 . In addition, p70S6 kinase phosphorylation (a downstream effector of mTORC1) was reduced when engineered muscle was cultured at 1% O2 , with no significant changes seen above this O2 level. Overall, these data suggest that engineered muscle exposed to O2 levels of ?5% adapts in a manner similar to that seen in COPD patients, and thus may provide a novel model for further understanding muscle wasting associated with tissue hypoxia. J. Cell. Biochem. 118: 2599-2605, 2017. © 2017 The Authors. Journal of Cellular Biochemistry Published by Wiley Periodicals, Inc.
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Project description:Highland native Andeans have resided at altitude for millennia. They display high aerobic capacity (VO2max) at altitude, which may be a reflection of genetic adaptation to hypoxia. Previous genomewide (GW) scans for natural selection have nominated Egl-9 homolog 1 gene (EGLN1) as a candidate gene. The encoded protein, EGLN1/PHD2, is an O2 sensor that controls levels of the Hypoxia Inducible Factor-? (HIF-?), which regulates the cellular response to hypoxia. From GW association and analysis of covariance performed on a total sample of 429 Peruvian Quechua and 94 US lowland referents, we identified 5 EGLN1 SNPs associated with higher VO2max (L?min-1 and mL?min-1?kg-1) in hypoxia (rs1769793, rs2064766, rs2437150, rs2491403, rs479200). For 4 of these SNPs, Quechua had the highest frequency of the advantageous (high VO2max) allele compared with 25 diverse lowland comparison populations from the 1000 Genomes Project. Genotype effects were substantial, with high versus low VO2max genotype categories differing by ?11% (e.g., for rs1769793 SNP genotype TT = 34.2 mL?min-1?kg-1 vs. CC = 30.5 mL?min-1?kg-1). To guard against spurious association, we controlled for population stratification. Findings were replicated for EGLN1 SNP rs1769793 in an independent Andean sample collected in 2002. These findings contextualize previous reports of natural selection at EGLN1 in Andeans, and support the hypothesis that natural selection has increased the frequency of an EGLN1 causal variant that enhances O2 delivery or use during exercise at altitude in Peruvian Quechua.
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Project description:Epidemiological studies reveal a strong link between low aerobic capacity and metabolic and cardiovascular diseases. Two-way artificial selection of rats based on low and high intrinsic exercise capacity has produced two strains that also differ in risk for metabolic syndrome (Koch LG, Britton SL. Artificial selection for intrinsic aerobic endurance running capacity in rats. Physiol Genomics 5:45-52, 2001). Here we investigated skeletal muscle characteristics and genotype-phenotype relationships behind high and low inherited aerobic exercise capacity and the link between oxygen metabolism and metabolic disease risk factors in rats derived from generation 18. This population (n=24) of high capacity runners (HCR) and low capacity runners (LCR) differed by 615% in maximal treadmill running capacity. LCR were significantly significantly heavier and had increased blood glucose, serum insulin and triglyceride concentration. HCR had higher resting metabolic rate than LCR. Capillaries/mm2 and capillary-to-fiber ratio were significantly greater in HCR rats in soleus and gastrocnemius and capillary-to-fiber ratio in extensor digitorum longus (EDL) muscle. Subsarcolemmal mitochondrial area was 96% (p<0.01) and intermyofibrillar area was 32% (p<0.05) larger in HCR soleus. Microarray results showed that 126 genes were significantly up-regulated and 113 genes were down-regulated in HCR (p<0.05). Functional clustering and unbiased correlation analysis of muscle microarray data revealed that genes up-regulated in HCR were related to mitochondria, carboxylic acid and lipid metabolism, and oxidoreductase activity. In conclusion, our data show that aerobic capacity is strongly linked to the architecture of energy transfer and corroborate the importance of oxygen metabolism as the determinant of metabolic health and complex metabolic diseases such as metabolic syndrome and type 2 diabetes.
2010-04-01 | GSE17190 | GEO
Project description:Maternal obesity is proposed to alter the programming of metabolic systems in the offspring, increasing the risk for developing metabolic diseases; however, the cellular mechanisms remain poorly understood. Here, we used a nonhuman primate model to examine the impact of a maternal Western-style diet (WSD) alone, or in combination with obesity (Ob/WSD), on fetal skeletal muscle metabolism studied in the early third trimester. We find that fetal muscle responds to Ob/WSD by upregulating fatty acid metabolism, mitochondrial complex activity, and metabolic switches (CPT-1, PDK4) that promote lipid utilization over glucose oxidation. Ob/WSD fetuses also had reduced mitochondrial content, diminished oxidative capacity, and lower mitochondrial efficiency in muscle. The decrease in oxidative capacity and glucose metabolism was persistent in primary myotubes from Ob/WSD fetuses despite no additional lipid-induced stress. Switching obese mothers to a healthy diet prior to pregnancy did not improve fetal muscle mitochondrial function. Lastly, while maternal WSD alone led only to intermediary changes in fetal muscle metabolism, it was sufficient to increase oxidative damage and cellular stress. Our findings suggest that maternal obesity or WSD, alone or in combination, leads to programmed decreases in oxidative metabolism in offspring muscle. These alterations may have important implications for future health.
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Project description:A reduction in aerobic capacity and the shortening of telomeres are hallmarks of the ageing process. We examined whether a lower aerobic capacity is associated with shorter TL in skeletal muscle and/or leukocytes, across a wide age range of individuals. We also tested whether TL in human skeletal muscle (MTL) correlates with TL in leukocytes (LTL). Eighty-two recreationally active, healthy men from the Gene SMART cohort (31.4±8.2 years; body mass index (BMI)=25.3±3.3kg/m2), and 11 community dwelling older men (74.2±7.5years-old; BMI=28.7±2.8kg/m2) participated in the study. Leukocytes and skeletal muscle samples were collected at rest. Relative telomere length (T/S ratio) was measured by RT-PCR. Associations between TL, aerobic capacity (VO2 peak and peak power) and age were assessed with robust linear models. Older age was associated with shorter LTL (45% variance explained, P<0.001), but not MTL (P= 0.7). Aerobic capacity was not associated with MTL (P=0.5), nor LTL (P=0.3). MTL and LTL were correlated across the lifespan (rs=0.26, P=0.03). In healthy individuals, age explain most of the variability of LTL and this appears to be independent of individual aerobic capacity. Individuals with longer LTL also have a longer MTL, suggesting that there might be a shared molecular mechanism regulating telomere length.
| S-EPMC6977669 | biostudies-literature
Project description:BackgroundIndividuals with glycogen storage disease IIIa (GSD IIIa) (OMIM #232400) experience muscle weakness and exercise limitation that worsen through adulthood. However, normative data for markers of physical capacity, such as strength and cardiovascular fitness, are limited. Furthermore, the impact of the disease on muscle size and quality is unstudied in weight bearing skeletal muscle, a key predictor of physical function. We aim to produce normative reference values of aerobic capacity and strength in individuals with GSD IIIa, and to investigate the role of muscle size and quality on exercise impairment.ResultsPeak oxygen uptake (V̇O2peak) was lower in the individuals with GSD IIIa than predicted based on demographic data (17.0 (9.0) ml/kg/min, 53 (24)% of predicted, p = 0.001). Knee extension maximum voluntary contraction (MVC) was also substantially lower than age matched predicted values (MVC: 146 (116) Nm, 57% predicted, p = 0.045), though no difference was found in MVC relative to body mass (1.88 (2.74) Nm/kg, 61% of predicted, p = 0.263). There was a strong association between aerobic capacity and maximal leg strength (r = 0.920; p = 0.003). Substantial inter-individual variation was present, with a high physical capacity group that had normal leg strength (MVC), and relatively high V̇O2peak, and a low physical capacity that display impaired strength and substantially lower V̇O2peak. The higher physical capacity sub-group were younger, had larger Vastus Lateralis (VL) muscles, greater muscle quality, undertook more physical activity (PA), and reported higher health-related quality of life.ConclusionsV̇O2peak and knee extension strength are lower in individuals with GSD IIIa than predicted based on their demographic data. Patients with higher physical capacity have superior muscle size and structure characteristics and higher health-related quality of life, than those with lower physical capacity. This study provides normative values of these important markers of physical capacity.
| S-EPMC8802498 | biostudies-literature
Project description:Mitochondrial diseases are genetic disorders that lead to impaired mitochondrial function, resulting in exercise intolerance and muscle weakness. In patients, muscle fatigue due to defects in mitochondrial oxidative capacities commonly precedes muscle weakness. In mice, deletion of the fast-twitch skeletal muscle-specific Tfam gene (Tfam KO) leads to a deficit in respiratory chain activity, severe muscle weakness and early death. Here, we performed a time-course study of mitochondrial and muscular dysfunctions in 11- and 14-week-old Tfam KO mice, i.e. before and when mice are about to enter the terminal stage, respectively. Although force in the unfatigued state was reduced in Tfam KO mice compared to control littermates (wild type) only at 14 weeks, during repeated submaximal contractions fatigue was faster at both ages. During fatiguing stimulation, total phosphocreatine breakdown was larger in Tfam KO muscle than in wild-type muscle at both ages, whereas phosphocreatine consumption was faster only at 14 weeks. In conclusion, the Tfam KO mouse model represents a reliable model of lethal mitochondrial myopathy in which impaired mitochondrial energy production and premature fatigue occur before muscle weakness and early death.
| S-EPMC8461820 | biostudies-literature