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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 ∼20-70% 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.

BACKGROUND: Phenotypic frailty syndrome identifies older adults at greater risk for adverse health outcomes. Despite the critical role of mitochondria in maintaining cellular function, including energy production, the associations between muscle mitochondrial energetics and frailty have not been widely explored in a large, well-phenotyped, older population. METHODS: The Study of Muscle, Mobility and Aging (SOMMA) assessed muscle energetics in older adults (N = 879, mean age = 76.3 years, 59.2% women). 31Phosporous magnetic resonance spectroscopy measured maximal production of adenosine triphosphate (ATPmax) in vivo, while ex vivo high-resolution respirometry of permeabilized muscle fibers from the vastus lateralis measured maximal oxygen consumption supported by fatty acids and complex I- and II-linked carbohydrates (e.g., Max OXPHOSCI+CII). Five frailty criteria, shrinking, weakness, exhaustion, slowness, and low activity, were used to classify participants as robust (0, N = 397), intermediate (1-2, N = 410), or frail (≥ 3, N = 66). We estimated the proportional odds ratio (POR) for greater frailty, adjusted for multiple potential confounders. RESULTS: One-SD decrements of most respirometry measures (e.g., Max OXPHOSCI+CII, adjusted POR = 1.5, 95%CI [1.2,1.8], p = 0.0001) were significantly associated with greater frailty classification. The associations of ATPmax with frailty were weaker than those between Max OXPHOSCI+CII and frailty. Muscle energetics was most strongly associated with slowness and low physical activity components. CONCLUSIONS: Our data suggest that deficits in muscle mitochondrial energetics may be a biological driver of frailty in older adults. On the other hand, we did observe differential relationships between measures of muscle mitochondrial energetics and the individual components of frailty.

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.

BackgroundFalls 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.MethodsIn 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 one year. Skeletal muscle energetics were assessed at baseline in vivo using 31P Magnetic Resonance Spectroscopy (MRS) after an acute bout of exercise (ATPmax) and ex vivo by High Resolution Respirometry (HRR) of permeabilized muscle fibers from the vastus lateralis (MaxOXPHOS).ResultsAt least one 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 400m walk gait speed (1.0 ± 0.2 vs. 1.1 ± 0.2, p

Oxidative stress is considered a contributor to declining muscle function and mobility during aging; however, the underlying molecular mechanisms remain poorly described. We hypothesized that greater levels of cysteine (Cys) oxidation on muscle proteins are associated with decreased measures of mobility. Herein, we applied a novel redox proteomics approach to measure reversible protein Cys oxidation in vastus lateralis muscle biopsies collected from 56 subjects in the Study of Muscle, Mobility and Aging (SOMMA), a community‐based cohort study of individuals aged 70 years and older. We tested whether levels of Cys oxidation on key muscle proteins involved in muscle structure and contraction were associated with muscle function (leg power and strength), walking speed, and fitness (VO2 peak on cardiopulmonary exercise testing) using linear regression models adjusted for age, sex, and body weight. Higher oxidation levels of select nebulin Cys sites were associated with lower VO2 peak, while greater oxidation of myomesin‐1, myomesin‐2, and nebulin Cys sites was associated with slower walking speed. Higher oxidation of Cys sites in key proteins such as myomesin‐2, alpha‐actinin‐2, and skeletal muscle alpha‐actin were associated with lower leg power and strength. We also observed an unexpected correlation (R = 0.48) between a higher oxidation level of eight Cys sites in alpha‐actinin‐3 and stronger leg power. Despite this observation, the results generally support the hypothesis that Cys oxidation of muscle proteins impairs muscle power and strength, walking speed, and cardiopulmonary fitness with aging. [ABSTRACT FROM AUTHOR]

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: Women = 55.06 ± 15.95; Men = 65.80 ± 19.74; p  < .001) and in individuals with mobility impairment compared to those without (eg, Maximal Complex I&II OXPHOS in women: SPPB ≥ 9 = 56.59 ± 16.22; SPPB ≤ 8 = 47.37 ± 11.85; p  < .001). Muscle energetics were negatively associated with age only in men (eg, Maximal ETS capacity: R  = −0.15, p  = .02; age/sex interaction, p  = .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-adjusted = 1.78, 95% confidence interval [CI] = 1.03, 3.08, p  = .038; 80+ age group, ORage-adjusted = 1.05, 95% CI = 0.52, 2.15, p  = .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. [ABSTRACT FROM AUTHOR]

Objective Methods Results Conclusion 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.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.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.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. [ABSTRACT FROM AUTHOR]

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.