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Findings from the Study of Muscle, Mobility and Aging (SOMMA) in this issue of Aging Cell show that several biological pathways in skeletal muscle cells play an important role in determining mobility in older adults. These are based on assays in skeletal muscle biopsies obtained from participants, aged 70 years and older in SOMMA tested for association with assessments related to mobility, including muscle mass, strength, power, cardiopulmonary fitness, and 400 m walking speed. The papers show that, using mass spectrometry, oxidative modifications of proteins essential to myocellular function are associated with poorer mobility. Using RNA-seq to quantify gene expression, lower levels of expression of antioxidant enzymes located in mitochondria, autophagy, patterns of expression of genes involved in autophagy, and higher levels of RNA transcripts that increase with denervation were associated with poorer performance on tests of mobility. These results extend previous research from the Baltimore Longitudinal Study of Aging and recent studies from SOMMA showing the importance of mitochondrial energetics in mobility. Together, these findings are painting a picture of how fundamental cellular processes influence the loss of mobility with aging. They may also be a window on aging in other cells, tissues, and systems. The data collected in SOMMA are publicly available and SOMMA welcomes collaborations with scientists who are interested in research about human aging.
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Envelhecimento , Humanos , Envelhecimento/fisiologia , Envelhecimento/metabolismo , Idoso , Músculo Esquelético/metabolismoRESUMO
BACKGROUND: Cardiopulmonary exercise testing (CPET), the gold-standard method to quantify cardiorespiratory fitness (CRF), is not always feasible due to cost, access, and burden. The usual-paced 400 m long distance corridor walk (LDCW), a measure of mobility among older adults, may provide an alternate method to assess CRF. The purpose of this study was to develop and validate an estimating equation to estimate VO2 peak from average 400 m walking speed (WS) among participants in the Study of Muscle, Mobility and Aging (SOMMA). METHODS: At baseline, women (58%) and men age 70 years and older enrolled in SOMMA (N = 820, 76.2 ± 4.9 years, 86% Non-Hispanic White) completed a 400 m LDCW (400 m WS = 400 m/completion time in seconds) and symptom-limited maximal CPET (Modified Balke Protocol). VO2 peak (mL/kg/min) was considered the highest 30-second average oxygen consumption during CPET. Other covariates included: age, sex, race, physical activity (7-day wrist-worn accelerometer), physical function (Short Physical Performance Battery, range 0-12), perceived physical fatigability (Pittsburgh Fatigability Scale, range 0-50), and Borg Rating of Perceived Exertion (RPE, range 6-20) at completion of the 400 m LDCW. Stepwise linear regression was used. Internal validation was completed using data-splitting method (70%; 30%). RESULTS: Mean VO2 peak was 20.2 ± 4.8 mL/kg/min and mean 400 m WS was 1.06 ± 0.2 m/s. Each 0.05 m/s increment in 400 m WS was associated with a 0.40 mL/kg/min higher VO2 peak after covariate adjustment. An estimating equation including 400 m WS, age, sex, race, and RPE was developed. Internal validation showed low overall bias (-0.26) and strong correlation (r = 0.71) between predicted and measured VO2 peak values. Bland-Altman plot and regression analyses indicated predicted VO2 peak was an acceptable alternative, despite mean underestimation of 4.53 mL/kg/min among the highly fit. CONCLUSIONS: Usual-paced 400 m LDCW strongly correlates with direct measures of CRF during CPET in older adults with lower fitness and can be used to test both fitness and function.
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Aptidão Cardiorrespiratória , Masculino , Humanos , Feminino , Idoso , Envelhecimento , Caminhada/fisiologia , Teste de Esforço , Fadiga , Músculos , Consumo de Oxigênio/fisiologiaRESUMO
BACKGROUND: Walking slows with aging often leading to mobility disability. Mitochondrial energetics has been found to be associated with gait speed over short distances. Additionally, walking is a complex activity but few clinical factors that may be associated with walk time have been studied. METHODS: We examined 879 participants ≥70 years and measured the time to walk 400 m. We tested the hypothesis that decreased mitochondrial energetics by respirometry in muscle biopsies and magnetic resonance spectroscopy in the thigh and is associated with longer time to walk 400 m. We also used cardiopulmonary exercise testing to assess the energetic costs of walking: maximum oxygen consumption (VO2peak) and energy cost-capacity (the ratio of VO2, at a slow speed to VO2peak). In addition, we tested the hypothesis that selected clinical factors would also be associated with 400-m walk time. RESULTS: Lower Max OXPHOS was associated with longer walk time, and the association was explained by the energetic costs of walking, leg power, and weight. Additionally, a multivariate model revealed that longer walk time was also significantly associated with lower VO2peak, greater cost-capacity ratio, weaker leg power, heavier weight, hip and knee stiffness, peripheral neuropathy, greater perceived exertion while walking slowly, greater physical fatigability, less moderate-to-vigorous exercise, less sedentary time, and anemia. Significant associations between age, sex, muscle mass, and peripheral artery disease with 400-m walk time were explained by other clinical and physiologic factors. CONCLUSIONS: Lower mitochondrial energetics is associated with needing more time to walk 400 m. This supports the value of developing interventions to improve mitochondrial energetics. Additionally, doing more moderate-to-vigorous exercise, increasing leg power, reducing weight, treating hip and knee stiffness, and screening for and treating anemia may reduce the time required to walk 400 m and reduce the risk of mobility disability.
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Anemia , Caminhada , Humanos , Envelhecimento/fisiologia , Exercício Físico , Músculo Esquelético , Caminhada/fisiologia , IdosoRESUMO
BACKGROUND: The effects of aging on circadian patterns of behavior are insufficiently described. To address this, we characterized age-specific features of rest-activity rhythms (RAR) in community-dwelling older adults both overall, and in relation, to sociodemographic characteristics. METHODS: We examined cross-sectional associations between RAR and age, sex, race, education, multimorbidity burden, financial, work, martial, health, and smoking status using assessments of older adults with wrist-worn free-living actigraphy data (Nâ =â 820, ageâ =â 76.4 years, 58.2% women) participating in the Study of Muscle, Mobility, and Aging (SOMMA). RAR parameters were determined by mapping an extension to the traditional cosine curve to activity data. Functional principal component analysis determined variables accounting for variance. RESULTS: Age was associated with several metrics of dampened RAR; women had stronger and more robust RAR versus men (all pâ <â .05). Total activity (56%) and time of activity (20%) accounted for most of the RAR variance. Compared to the latest decile of acrophase, those in the earliest decile had higher average amplitude (pâ <â .001). Compared to the latest decile of acrophase, those in the earliest and midrange categories had more total activity (pâ =â .02). Being in a married-like relationship and a more stable financial situation were associated with stronger rhythms; higher education was associated with less rhythm strength (all pâ <â .05). CONCLUSIONS: Older age was associated with dampened circadian behavior; behaviors were sexually dimorphic. Some sociodemographic characteristics were associated with circadian behavior. We identified a behavioral phenotype characterized by early time of day of peak activity, high rhythmic amplitude, and more total activity.
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Ritmo Circadiano , Descanso , Masculino , Humanos , Feminino , Idoso , Estudos Transversais , Descanso/fisiologia , Ritmo Circadiano/fisiologia , Envelhecimento/fisiologia , Actigrafia , Músculos , Sono/fisiologiaRESUMO
BACKGROUND: Muscle mass loss may be associated with liver fat accumulation, yet scientific consensus is lacking and evidence in older adults is scant. It is unclear which muscle characteristics might contribute to this association in older adults. METHODS: We associated comprehensive muscle-related phenotypes including muscle mass normalized to body weight (D3-creatine dilution), muscle fat infiltration (magnetic resonance imaging), carbohydrate-supported muscle mitochondrial maximal oxidative phosphorylation (respirometry), and cardiorespiratory fitness (VO2 peak) with liver fat among older adults. Linear regression models adjusted for age, gender, technician (respirometry only), daily minutes of moderate-to-vigorous physical activity, and prediabetes/diabetes status tested main effects and interactions of each independent variable with waist circumference (high: women-≥88 cm, men-≥102 cm) and gender. RESULTS: Among older adults aged 75 (interquartile range: 73, 79 years; 59.8% women), muscle mass and liver fat were not associated overall (Nâ =â 362) but were positively associated among participants with a high waist circumference (ß: 25.2; 95% confidence intervals [95% CI]: 11.7, 40.4; pâ =â .0002; Nâ =â 160). Muscle fat infiltration and liver fat were positively associated (ß: 15.2; 95% CI: 6.8, 24.3; pâ =â .0003; Nâ =â 378). Carbohydrate-supported maximum oxidative phosphorylation (before adjustment) and VO2 peak (after adjustment; ß: -12.9; 95% CI: -20.3, -4.8; pâ =â .003; Nâ =â 361) were inversely associated with liver fat; adjustment attenuated the estimate for maximum oxidative phosphorylation although the point estimate remained negative (ß: -4.0; 95% CI: -11.6, 4.2; pâ =â .32; Nâ =â 321). CONCLUSIONS: Skeletal muscle-related characteristics are metabolically relevant factors linked to liver fat in older adults. Future research should confirm our results to determine whether trials targeting mechanisms common to liver and muscle fat accumulation are warranted.
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Aptidão Cardiorrespiratória , Masculino , Humanos , Feminino , Idoso , Músculo Esquelético/fisiologia , Peso Corporal , Fígado , CarboidratosRESUMO
BACKGROUND: How magnetic resonance (MR) derived thigh muscle volume and deuterated creatine dilution derived muscle mass (D3Cr muscle mass) differentially relate to strength, fitness, and other functions in older adults-and whether associations vary by sex-is not known. METHODS: Men (Nâ =â 345) and women (Nâ =â 482) aged ≥70 years from the Study of Muscle, Mobility, and Aging completed leg extension strength (1-repetition max) and cardiopulmonary exercise testing to assess fitness (VO2peak). Correlations and adjusted regression models stratified by sex were used to assess the association between muscle size measures, study outcomes, and sex interactions. RESULTS: D3Cr muscle mass and MR thigh muscle volume were correlated (men: râ =â 0.62, women: râ =â 0.51, pâ <â .001). Each standard deviation (SD) decrement in D3Cr muscle mass was associated with lower 1-repetition max strength (-14 kg men, -4 kg women, pâ <â .001 for both; p-interactionâ =â .003) and lower VO2peak (-79 mL/min men, -30 mL/min women, pâ <â .001 for both, p-interaction: .016). Each SD decrement in MR thigh muscle volume was also associated with lower strength (-32 kg men, -20 kg women, pâ <â .001 for both; p-interactionâ =â .139) and lower VO2peak (-217 mL/min men, -111 mL/min women, pâ <â .001 for both, p-interactionâ =â .010). There were associations, though less consistent, between muscle size or mass with physical performance and function; associations varied by sex. CONCLUSIONS: Less muscle-measured by either D3Cr muscle mass or MR thigh muscle volume-was associated with lower strength and fitness. Varied associations by sex and assessment method suggest consideration be given to which measurement to use in future studies.
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Músculo Esquelético , Coxa da Perna , Masculino , Humanos , Feminino , Idoso , Músculo Esquelético/fisiologia , Envelhecimento/fisiologia , Desempenho Físico Funcional , Espectroscopia de Ressonância Magnética , Força Muscular/fisiologiaRESUMO
BACKGROUND: Falls in the older population are a major public health concern. While many physiological and environmental factors have been associated with fall risk, muscle mitochondrial energetics has not yet been investigated. METHODS: In this analysis, 835 Study of Muscle, Mobility and Aging (SOMMA) participants aged 70-94 were surveyed for number of falls (total), recurrent falls (2+), and fall-related injuries over the past 12 months at baseline and again after 1 year. Skeletal muscle energetics were assessed at baseline in vivo using 31P Magnetic Resonance Spectroscopy for the maximal rate of adenosine triphosphate recovery (ATPmax) after an acute bout of exercise, and ex vivo by High-Resolution Respirometry for the maximal rate of complex I and II supported oxygen consumption (MaxOXPHOS) in permeabilized muscle fibers from the vastus lateralis. RESULTS: At least 1 fall was reported in 28.7% of SOMMA participants in the first year of the study, with 12% of older adults reporting recurrent falls (2+). Individuals who experienced recurrent falls had a slower 400-m walk gait speed (1.0 ± 0.2 vs 1.1 ± 0.2, p < .001), reported fewer alcoholic drinks per week in the past year (2.4 ± 4.3 vs 2.8 ± 4.4, p = .054), and took a significantly greater number of medication in the 30 days before their baseline visit (5.6 ± 4.4 vs 4.2 ± 3.4, p < .05). A history of falls was reported in 63% of individuals who experienced recurrent falls in the first year of the study compared to 22.8% who experienced 1 or fewer falls. MaxOXPHOS was significantly lower in those who reported recurrent falls (p = .008) compared to those with 1 or fewer falls, but there was no significant difference in ATPmax (p = .369). Neither muscle energetics measure was significantly associated with total number of falls or injurious falls, but recurrent falls were significantly higher with lower MaxOXPHOS (risk ratio = 1.33, 95% confidence interval = 1.02-1.73, p = .033). However, covariates accounted for the increased risk. CONCLUSIONS: Mitochondrial energetics were largely unrelated to fall risk in older adults when accounting for variables, suggesting that the complex etiology of falls may not be related to a single "hallmark of aging" biological pathway.
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Envelhecimento , Músculo Esquelético , Humanos , Idoso , Músculo Esquelético/metabolismo , Exercício Físico , CaminhadaRESUMO
BACKGROUND: Slower gait speed may be driven by greater energy deficits and fatigability among older adults. We examined associations of walking energetics and perceived physical fatigability with gait speed among slower and faster walkers. Additionally, we used statistical mediation to examine the role of fatigability in the associations of walking energetics and gait speed using the Study of Muscle, Mobility and Aging (SOMMA). METHODS: Perceived physical fatigability was assessed using the Pittsburgh Fatigability Scale (PFS) Physical score (range 0-50, higherâ =â greater). A 3-phase cardiopulmonary exercise treadmill test collected peak oxygen consumption (VO2peak, mL/kg/min), energetic cost of walking (ECW, mL/kg/m), and cost-capacity ratio (VO2/VO2peak*100, %). Slower (<1.01 m/s) versus faster (≥1.01 m/s) walkers were classified using median 4-m gait speed. Linear regressions and statistical mediation analyses were conducted. RESULTS: Slower walkers had lower VO2peak, higher ECW at preferred walking speed (PWS), and greater PFS Physical score compared to faster walkers (all pâ <â .05; Nâ =â 849). One standard deviation (1-SD) higher VO2peak was associated with 0.1 m/s faster gait speed, while 1-SD higher ECW PWS, cost-capacity ratio at PWS and slow walking speed (SWS), and PFS Physical score were associated with 0.02-0.23 m/s slower gait speed. PFS Physical score was a significant statistical mediator in the associations between VO2peak (15.2%), SWS cost-capacity ratio (15.9%), and ECW PWS (10.7%) with gait speed and was stronger among slower walkers. CONCLUSIONS: Slower walkers may be more influenced by perceptions of fatigue in addition to walking energetics. Our work highlights the importance of targeting both energetics and perceived fatigability to prevent mobility decline.
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Metabolismo Energético , Fadiga , Consumo de Oxigênio , Velocidade de Caminhada , Caminhada , Humanos , Masculino , Velocidade de Caminhada/fisiologia , Feminino , Idoso , Metabolismo Energético/fisiologia , Consumo de Oxigênio/fisiologia , Fadiga/fisiopatologia , Caminhada/fisiologia , Teste de Esforço/métodos , Envelhecimento/fisiologia , Pessoa de Meia-Idade , Idoso de 80 Anos ou maisRESUMO
AIM: High-resolution respirometry in human permeabilized muscle fibers is extensively used for analysis of mitochondrial adaptions to nutrition and exercise interventions, and is linked to athletic performance. However, the lack of standardization of experimental conditions limits quantitative inter- and intra-laboratory comparisons. METHODS: In our study, an international team of investigators measured mitochondrial respiration of permeabilized muscle fibers obtained from three biopsies (vastus lateralis) from the same healthy volunteer to avoid inter-individual variability. High-resolution respirometry assays were performed together at the same laboratory to assess whether the heterogenity in published results are due to the effects of respiration media (MiR05 versus Z) with or without the myosin inhibitor blebbistatin at low- and high-oxygen regimes. RESULTS: Our findings reveal significant differences between respiration media for OXPHOS and ETcapacities supported by NADH&succinate-linked substrates at different oxygen concentrations. Respiratory capacities were approximately 1.5-fold higher in MiR05 at high-oxygen regimes compared to medium Z near air saturation. The presence or absence of blebbistatin in human permeabilized muscle fiber preparations was without effect on oxygen flux. CONCLUSION: Our study constitutes a basis to harmonize and establish optimum experimental conditions for respirometric studies of permeabilized human skeletal muscle fibers to improve reproducibility.
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OBJECTIVE: Our objective was to investigate the overall and sex-specific relationships between the presence and severity of knee osteoarthritis (KOA) and muscle composition, power, and energetics in older adults. METHODS: Male and female patients (n = 655, mean ± SD age 76.1 ± 4.9 years; 57% female) enrolled in the Study of Muscle, Mobility, and Aging completed standing knee radiographs and knee pain assessments. Participants were divided into three groups using Kellgren-Lawrence grade (KLG) of KOA severity (0-1, 2, or 3-4). Outcome measures included whole-body muscle mass, thigh fat-free muscle (FFM) volume and muscle fat infiltration (MFI), leg power, specific power (power normalized to muscle volume), and muscle mitochondrial energetics. RESULTS: Overall, the presence and severity of KOA is associated with greater MFI, lower leg power and specific power, and reduced oxidative phosphorylation (P trend < 0.036). Sex-specific analysis revealed reduced energetics only in female patients with KOA (P trend < 0.007) compared to female patients without KOA. In models adjusted for age, sex, race, nonsteroidal anti-inflammatory drug administration, site or technician, physical activity, height, and participants with abdominal adiposity with KLG 3 to 4 had greater MFI (mean 0.008%, 95% confidence interval [CI] 0.004%-0.011%) and lower leg power (mean -51.56 W, 95% CI -74.03 to -29.10 W) and specific power (mean -5.38 W/L, 95% CI -7.31 to -3.45 W/L) than those with KLG 0 to 1. No interactions were found between pain and KLG status. Among those with KOA, MFI and oxidative phosphorylation were associated with thigh FFM volume, leg power, and specific power. CONCLUSION: Muscle health is associated with the presence and severity of KOA and differs by sex. Although muscle composition and power are lower in both male and female patients with KOA, regardless of pain status, mitochondrial energetics is reduced only in female patients.
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The age-related decline in muscle mitochondrial energetics contributes to the loss of mobility in older adults. Women experience a higher prevalence of mobility impairment compared to men, but it is unknown whether sex-specific differences in muscle energetics underlie this disparity. In the Study of Muscle, Mobility and Aging (SOMMA), muscle energetics were characterized using in vivo phosphorus-31 magnetic resonance spectroscopy and high-resolution respirometry of vastus lateralis biopsies in 773 participants (56.4% women, age 70-94 years). A Short Physical Performance Battery (SPPB) score ≤8 was used to define lower-extremity mobility impairment. Muscle mitochondrial energetics were lower in women compared to men (eg, Maximal Complex I&II OXPHOS: Womenâ =â 55.06 ± 15.95; Menâ =â 65.80 ± 19.74; pâ <â .001) and in individuals with mobility impairment compared to those without (eg, Maximal Complex I&II OXPHOS in women: SPPBâ ≥â 9â =â 56.59 ± 16.22; SPPBâ ≤â 8â =â 47.37 ± 11.85; pâ <â .001). Muscle energetics were negatively associated with age only in men (eg, Maximal ETS capacity: Râ =â -0.15, pâ =â .02; age/sex interaction, pâ =â .04), resulting in muscle energetics measures that were significantly lower in women than men in the 70-79 age group but not the 80+ age group. Similarly, the odds of mobility impairment were greater in women than men only in the 70-79 age group (70-79 age group, odds ratio [OR]age-adjustedâ =â 1.78, 95% confidence interval [CI]â =â 1.03, 3.08, pâ =â .038; 80+ age group, ORage-adjustedâ =â 1.05, 95% CIâ =â 0.52, 2.15, pâ =â .89). Accounting for muscle energetics attenuated up to 75% of the greater odds of mobility impairment in women. Women had lower muscle mitochondrial energetics compared to men, which largely explain their greater odds of lower-extremity mobility impairment.
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Envelhecimento , Músculo Esquelético , Masculino , Humanos , Feminino , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/fisiologia , Músculo Quadríceps , Extremidade InferiorRESUMO
Social stress experienced in childhood is associated with adverse health later in life. Mitochondrial function has been implicated as a mechanism for how stressful life events "get under the skin" to influence physical well-being. Using data from the Study of Muscle, Mobility, and Aging (n = 879, 59% women), linear models examined whether adverse childhood events (i.e., physical abuse) were associated with two measures of skeletal muscle mitochondrial energetics in older adults: (i) maximal adenosine triphosphate production (ATPmax) and (ii) maximal state 3 respiration (Max OXPHOS). Forty-five percent of the sample reported experiencing one or more adverse childhood events. After adjustment, each additional event was associated with -0.08 SD (95% confidence interval = -0.13, -0.02) lower ATPmax. No association was observed with Max OXPHOS. Adverse childhood events are associated with lower ATP production in later life. Findings indicate that mitochondrial function may be a mechanism for understanding how early social stress influences health in later life.
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Músculo Esquelético , Fenômenos Fisiológicos Musculoesqueléticos , Feminino , Humanos , Idoso , Masculino , Trifosfato de Adenosina , Envelhecimento , MitocôndriasRESUMO
Gene expression in skeletal muscle of older individuals may reflect compensatory adaptations in response to oxidative damage that preserve tissue integrity and maintain function. Identifying associations between oxidative stress response gene expression patterns and mitochondrial function, physical performance, and muscle mass in older individuals would further our knowledge of mechanisms related to managing molecular damage that may be targeted to preserve physical resilience. To characterize expression patterns of genes responsible for the oxidative stress response, RNA was extracted and sequenced from skeletal muscle biopsies collected from 575 participants (≥70 years old) from the Study of Muscle, Mobility, and Aging. Expression levels of 21 protein-coding RNAs related to the oxidative stress response were analyzed in relation to six phenotypic measures, including maximal mitochondrial respiration from muscle biopsies (Max OXPHOS), physical performance (VO2 peak, 400-m walking speed, and leg strength), and muscle size (thigh muscle volume and whole-body D3Cr muscle mass). The mRNA level of the oxidative stress response genes most consistently associated across outcomes are preferentially expressed within the mitochondria. Higher expression of mRNAs that encode generally mitochondria located proteins SOD2, TRX2, PRX3, PRX5, and GRX2 were associated with higher levels of mitochondrial respiration and VO2 peak. In addition, greater SOD2, PRX3, and GRX2 expression was associated with higher physical performance and muscle size. Identifying specific mechanisms associated with high functioning across multiple performance and physical domains may lead to targeted antioxidant interventions with greater impacts on mobility and independence.
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Envelhecimento , Músculo Esquelético , Estresse Oxidativo , Humanos , Estresse Oxidativo/genética , Idoso , Envelhecimento/genética , Envelhecimento/metabolismo , Masculino , Músculo Esquelético/metabolismo , Feminino , Desempenho Físico Funcional , Mitocôndrias/metabolismo , Mitocôndrias/genética , Mitocôndrias Musculares/metabolismo , Mitocôndrias Musculares/genética , Idoso de 80 Anos ou maisRESUMO
With aging skeletal muscle fibers undergo repeating cycles of denervation and reinnervation. In approximately the 8th decade of life reinnervation no longer keeps pace, resulting in the accumulation of persistently denervated muscle fibers that in turn cause an acceleration of muscle dysfunction. The significance of denervation in important clinical outcomes with aging is poorly studied. The Study of Muscle, Mobility, and Aging (SOMMA) is a large cohort study with the primary objective to assess how aging muscle biology impacts clinically important traits. Using transcriptomics data from vastus lateralis muscle biopsies in 575 participants we have selected 49 denervation-responsive genes to provide insights to the burden of denervation in SOMMA, to test the hypothesis that greater expression of denervation-responsive genes negatively associates with SOMMA participant traits that included time to walk 400 meters, fitness (VO2peak), maximal mitochondrial respiration, muscle mass and volume, and leg muscle strength and power. Consistent with our hypothesis, increased transcript levels of: a calciumdependent intercellular adhesion glycoprotein (CDH15), acetylcholine receptor subunits (CHRNA1, CHRND, CHRNE), a glycoprotein promoting reinnervation (NCAM1), a transcription factor regulating aspects of muscle organization (RUNX1), and a sodium channel (SCN5A) were each negatively associated with at least 3 of these traits. VO2peak and maximal respiration had the strongest negative associations with 15 and 19 denervation-responsive genes, respectively. In conclusion, the abundance of denervationresponsive gene transcripts is a significant determinant of muscle and mobility outcomes in aging humans, supporting the imperative to identify new treatment strategies to restore innervation in advanced age.
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Envelhecimento , Músculo Esquelético , Humanos , Envelhecimento/genética , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/inervação , Idoso , Feminino , Pessoa de Meia-Idade , Estudos de Coortes , AdultoRESUMO
Autophagy is essential for proteostasis, energetic balance, and cell defense and is a key pathway in aging. Identifying associations between autophagy gene expression patterns in skeletal muscle and physical performance outcomes would further our knowledge of mechanisms related with proteostasis and healthy aging. Muscle biopsies were obtained from participants in the Study of Muscle, Mobility, and Aging (SOMMA). For 575 participants, RNA was sequenced and expression of 281 genes related to autophagy regulation, mitophagy, and mTOR/upstream pathways was determined. Associations between gene expression and outcomes including mitochondrial respiration in muscle fiber bundles (MAX OXPHOS), physical performance (VO2 peak, 400 m walking speed, and leg power), and thigh muscle volume, were determined using negative binomial regression models. For autophagy, key transcriptional regulators including TFE3 and NFKB-related genes (RELA, RELB, and NFKB1) were negatively associated with outcomes. On the contrary, regulators of oxidative metabolism that also promote overall autophagy, mitophagy, and pexophagy (PPARGC1A, PPARA, and EPAS1) were positively associated with multiple outcomes. In line with this, several mitophagy, fusion, and fission-related genes (NIPSNAP2, DNM1L, and OPA1) were also positively associated with outcomes. For mTOR pathway and related genes, expression of WDR59 and WDR24, both subunits of GATOR2 complex (an indirect inhibitor of mTORC1), and PRKAG3, which is a regulatory subunit of AMPK, were negatively correlated with multiple outcomes. Our study identifies autophagy and selective autophagy such as mitophagy gene expression patterns in human skeletal muscle related to physical performance, muscle volume, and mitochondrial function in older persons which may lead to target identification to preserve mobility and independence.
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Envelhecimento , Autofagia , Músculo Esquelético , Humanos , Músculo Esquelético/metabolismo , Autofagia/genética , Idoso , Masculino , Feminino , Envelhecimento/genética , Envelhecimento/metabolismo , Desempenho Físico Funcional , Mitocôndrias/metabolismo , Mitocôndrias/genética , Idoso de 80 Anos ou maisRESUMO
BACKGROUND: The geroscience hypothesis posits that aging biological processes contribute to many age-related deficits, including the accumulation of multiple chronic diseases. Though only one facet of mitochondrial function, declines in muscle mitochondrial bioenergetic capacities may contribute to this increased susceptibility to multimorbidity. METHODS: The Study of Muscle, Mobility and Aging (SOMMA) assessed ex vivo muscle mitochondrial energetics in 764 older adults (mean ageâ =â 76.4, 56.5% women, and 85.9% non-Hispanic White) by high-resolution respirometry of permeabilized muscle fibers. We estimated the proportional odds ratio (POR [95% CI]) for the likelihood of greater multimorbidity (4 levels: 0 conditions, Nâ =â 332; 1 condition, Nâ =â 299; 2 conditions, Nâ =â 98; or 3+ conditions, Nâ =â 35) from an index of 11 conditions, per SD decrement in muscle mitochondrial energetic parameters. Distribution of conditions allowed for testing the associations of maximal muscle energetics with some individual conditions. RESULTS: Lower oxidative phosphorylation supported by fatty acids and/or complex I- and II-linked carbohydrates (eg, Max OXPHOSCI+CII) was associated with a greater multimorbidity index score (PORâ =â 1.32 [1.13, 1.54]) and separately with diabetes mellitus (ORâ =â 1.62 [1.26, 2.09]), depressive symptoms (ORâ =â 1.45 [1.04, 2.00]) and possibly chronic kidney disease (ORâ =â 1.57 [0.98, 2.52]) but not significantly with other conditions (eg, cardiac arrhythmia, chronic obstructive pulmonary disease). CONCLUSIONS: Lower muscle mitochondrial bioenergetic capacities were associated with a worse composite multimorbidity index score. Our results suggest that decrements in muscle mitochondrial energetics may contribute to a greater global burden of disease and are more strongly related to some conditions than others.
Assuntos
Envelhecimento , Metabolismo Energético , Mitocôndrias Musculares , Multimorbidade , Humanos , Feminino , Idoso , Masculino , Metabolismo Energético/fisiologia , Mitocôndrias Musculares/metabolismo , Envelhecimento/metabolismo , Envelhecimento/fisiologia , Idoso de 80 Anos ou mais , Músculo Esquelético/metabolismoRESUMO
BACKGROUND: Skeletal muscle energetics decline with age, and physical activity (PA) has been shown to offset these declines in older adults. Yet, many studies reporting these effects were based on self-reported PA or structured exercise interventions. Therefore, we examined the associations of accelerometry-measured and self-reported PA and sedentary behavior (SB) with skeletal muscle energetics and explored the extent to which PA and sedentary behavior would attenuate the associations of age with muscle energetics. METHODS: As part of the Study of Muscle, Mobility and Aging, enrolled older adults (nâ¯=â¯879), 810 (ageâ¯=â¯76.4 ± 5.0 years old, mean ± SD; 58% women) had maximal muscle oxidative capacity measured ex vivo via high-resolution respirometry of permeabilized myofibers (maximal oxidative phosphorylation (maxOXPHOS)) and in vivo by 31phosphorus magnetic resonance spectroscopy (maximal adenosine triphosphate (ATPmax)). Accelerometry-measured sedentary behavior, light activity, and moderate-to-vigorous PA (MVPA) were assessed using a wrist-worn ActiGraph GT9X over 7 days. Self-reported sedentary behavior, MVPA, and all PA were assessed with the Community Healthy Activities Model Program for Seniors (CHAMPS) questionnaire. Linear regression models with progressive covariate adjustments evaluated the associations of sedentary behavior and PA with muscle energetics, as well as the attenuation of the age/muscle energetics association by MVPA and sedentary behavior. As a sensitivity analysis, we also examined activPAL-measured daily step count and time spent in sedentary behavior and their associations with muscle energetics. RESULTS: Every 30 min/day more of ActiGraph-measured MVPA was associated with 0.65 pmol/(s × mg) higher maxOXPHOS and 0.012 mM/s higher ATPmax after adjusting for age, site/technician, and sex (p < 0.05). Light activity was not associated with maxOXPHOS or ATPmax. Meanwhile, every 30 min/day spent in ActiGraph-measured sedentary behavior was associated with 0.39 pmol/sâ¯×â¯mg lower maxOXPHOS and 0.006 mM/s lower ATPmax (p < 0.05). Only associations with ATPmax held after further adjusting for socioeconomic status, body mass index, lifestyle factors, and multimorbidity. CHAMPS MVPA and all PA yielded similar associations with maxOXPHOS and ATPmax (p < 0.05), but sedentary behavior did not. Higher activPAL step count was associated with higher maxOXHPOS and ATPmax (p < 0.05), but time spent in sedentary behavior was not. Additionally, age was significantly associated with muscle energetics for men only (p < 0.05); adjusting for time spent in ActiGraph-measured MVPA attenuated the age association with ATPmax by 58% in men. CONCLUSION: More time spent in accelerometry-measured or self-reported daily PA, especially MVPA, was associated with higher skeletal muscle energetics. Interventions aimed specifically at increasing higher intensity activity might offer potential therapeutic interventions to slow age-related decline in muscle energetics. Our work also emphasizes the importance of taking PA into consideration when evaluating associations related to skeletal muscle energetics.
Assuntos
Acelerometria , Metabolismo Energético , Exercício Físico , Músculo Esquelético , Comportamento Sedentário , Autorrelato , Humanos , Idoso , Feminino , Masculino , Exercício Físico/fisiologia , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiologia , Metabolismo Energético/fisiologia , Idoso de 80 Anos ou mais , Envelhecimento/fisiologia , Envelhecimento/metabolismo , Fosforilação Oxidativa , Trifosfato de Adenosina/metabolismoRESUMO
Exercise mediates tissue metabolic function through direct and indirect adaptations to acylcarnitine (AC) metabolism, but the exact mechanisms are unclear. We found that circulating medium-chain acylcarnitines (AC) (C12-C16) are lower in active/endurance trained human subjects compared to sedentary controls, and this is correlated with elevated cardiorespiratory fitness and reduced adiposity. In mice, exercise reduced serum AC and increased liver AC, and this was accompanied by a marked increase in expression of genes involved in hepatic AC metabolism and mitochondrial ß-oxidation. Primary hepatocytes from high-fat fed, exercise trained mice had increased basal respiration compared to hepatocytes from high-fat fed sedentary mice, which may be attributed to increased Ca2+ cycling and lipid uptake into mitochondria. The addition of specific medium- and long-chain AC to sedentary hepatocytes increased mitochondrial respiration, mirroring the exercise phenotype. These data indicate that AC redistribution is an exercise-induced mechanism to improve hepatic function and metabolism.
RESUMO
Greater perceived physical fatigability and lower skeletal muscle energetics are predictors of mobility decline. Characterizing associations between muscle energetics and perceived fatigability may provide insight into potential targets to prevent mobility decline. We examined associations of in vivo (maximal ATP production, ATPmax) and ex vivo (maximal carbohydrate supported oxidative phosphorylation [max OXPHOS] and maximal fatty acid supported OXPHOS [max FAO OXPHOS]) measures of mitochondrial energetics with two measures of perceived physical fatigability, Pittsburgh Fatigability Scale (PFS, 0-50, higher=greater) and Rating of Perceived Exertion (RPE Fatigability, 6-20, higher=greater) after a slow treadmill walk. Participants from the Study of Muscle, Mobility and Aging (N=873) were 76.3±5.0 years old, 59.2% women, and 85.3% White. Higher muscle energetics (both in vivo and ex vivo ) were associated with lower perceived physical fatigability, all p<0.03. When stratified by sex, higher ATPmax was associated with lower PFS Physical for men only; higher max OXPHOS and max FAO OXPHOS were associated with lower RPE fatigability for both sexes. Higher skeletal muscle energetics were associated with 40-55% lower odds of being in the most (PFS≥25, RPE Fatigability≥12) vs least (PFS 0-4, RPE Fatigability 6-7) severe fatigability strata, all p<0.03. Being a woman was associated with 2-3 times higher odds of being in the most severe fatigability strata when controlling for ATPmax but not the in vivo measures (p<0.05). Better mitochondrial energetics were linked to lower fatigability and less severe fatigability in older adults. Findings imply that improving skeletal muscle energetics may mitigate perceived physical fatigability and prolong healthy aging.
RESUMO
Cardiorespiratory fitness and mitochondrial oxidative capacity are associated with reduced walking speed in older adults, but their impact on walking speed in older adults with diabetes has not been clearly defined. We examined differences in cardiorespiratory fitness and skeletal muscle mitochondrial oxidative capacity between older adults with and without diabetes, as well as determined their relative contribution to slower walking speed in older adults with diabetes. Participants with diabetes (n = 159) had lower cardiorespiratory fitness and mitochondrial respiration in permeabilized fiber bundles compared with those without diabetes (n = 717), following adjustments for covariates including BMI, chronic comorbid health conditions, and physical activity. Four-meter and 400-m walking speeds were slower in those with diabetes. Mitochondrial oxidative capacity alone or combined with cardiorespiratory fitness mediated â¼20-70% of the difference in walking speed between older adults with and without diabetes. Additional adjustments for BMI and comorbidities further explained the group differences in walking speed. Cardiorespiratory fitness and skeletal muscle mitochondrial oxidative capacity contribute to slower walking speeds in older adults with diabetes.