Associations between skeletal muscle energetics and accelerometry-based performance fatigability: Study of Muscle, Mobility and Aging.

Performance fatigability is typically experienced as insufficient energy to complete daily physical tasks, particularly with advancing age, often progressing toward dependency. Thus, understanding the etiology of performance fatigability, especially cellular-level biological mechanisms, may help to delay the onset of mobility disability. We hypothesized that skeletal muscle energetics may be important contributors to performance fatigability. Participants in the Study of Muscle, Mobility and Aging completed a usual-paced 400-m walk wearing a wrist-worn ActiGraph GT9X to derive the Pittsburgh Performance Fatigability Index (PPFI, higher scores = more severe fatigability) that quantifies percent decline in individual cadence-versus-time trajectory from their maximal cadence. Complex I&II-supported maximal oxidative phosphorylation (max OXPHOS) and complex I&II-supported electron transfer system (max ETS) were quantified ex vivo using high-resolution respirometry in permeabilized fiber bundles from vastus lateralis muscle biopsies. Maximal adenosine triphosphate production (ATPmax ) was assessed in vivo by 31 P magnetic resonance spectroscopy. We conducted tobit regressions to examine associations of max OXPHOS, max ETS, and ATPmax with PPFI, adjusting for technician/site, demographic characteristics, and total activity count over 7-day free-living among older adults (N = 795, 70-94 years, 58% women) with complete PPFI scores and ≥1 energetics measure. Median PPFI score was 1.4% [25th-75th percentile: 0%-2.9%]. After full adjustment, each 1 standard deviation lower max OXPHOS, max ETS, and ATPmax were associated with 0.55 (95% CI: 0.26-0.84), 0.39 (95% CI: 0.09-0.70), and 0.54 (95% CI: 0.27-0.81) higher PPFI score, respectively. Our findings suggested that therapeutics targeting muscle energetics may potentially mitigate fatigability and lessen susceptibility to disability among older adults.

Validation of the Pittsburgh Performance Fatigability Index in the Study of Muscle, Mobility and Aging.

BACKGROUND: The Pittsburgh Performance Fatigability Index (PPFI) quantifies the percent decline in cadence using accelerometry during standardized walking tasks. Although PPFI has shown strong correlations with physical performance, the developmental sample was relatively homogenous and small, necessitating further validation. METHODS: Participants from the Study of Muscle, Mobility and Aging (N = 805, age = 76.4 ±â€…5.0 years, 58% women, 85% White) wore an ActiGraph GT9X on the nondominant wrist during usual-paced 400 m walk. Tri-axial accelerations were analyzed to compute PPFI (higher score = greater fatigability). To evaluate construct and discriminant validity, Spearman correlations (rs) between PPFI and gait speed, Short Physical Performance Battery (SPPB), chair stand speed, leg peak power, VO2peak, perceived fatigability, and mood were examined. Sex-specific PPFI cut-points that optimally discriminated gait speed using classification and regression tree were then generated. Their discriminate power in relation to aforementioned physical performance were further evaluated. RESULTS: Median PPFI score was 1.4% (25th-75th percentile range: 0%-21.7%), higher among women than men (p < .001). PPFI score was moderate-to-strongly correlated with gait speed (rs = -0.75), SPPB score (rs = -0.38), chair stand speed (rs = -0.36), leg peak power (rs = -0.34) and VO2peak (rs = -0.40), and less strongly with perceived fatigability (rs = 0.28-0.29), all p < .001. PPFI score was not correlated with mood (|rs| < 0.08). Sex-specific PPFI cut-points (no performance fatigability: PPFI = 0%; mild performance fatigability: 0% < PPFI < 3.5% [women], 0% < PPFI < 5.4% [men]; moderate-to-severe performance fatigability: PPFI ≥ 3.5% [women], PPFI ≥ 5.4% [men]) discriminated physical performance (all p < .001), adjusted for demographics and smoking status. CONCLUSION: Our work underscores the utility of PPFI as a valid measure to quantify performance fatigability in future longitudinal epidemiologic studies and clinical/pharmaceutical trials.

Mitochondrial Energetics in Skeletal Muscle Are Associated With Leg Power and Cardiorespiratory Fitness in the Study of Muscle, Mobility and Aging.

BACKGROUND: Mitochondrial energetics are an important property of aging muscle, as generation of energy is pivotal to the execution of muscle contraction. However, its association with functional outcomes, including leg power and cardiorespiratory fitness, is largely understudied. METHODS: In the Study of Muscle, Mobility, and Aging, we collected vastus lateralis biopsies from older adults (n = 879, 70-94 years, 59.2% women). Maximal State 3 respiration (Max OXPHOS) was assessed in permeabilized fiber bundles by high-resolution respirometry. Capacity for maximal adenosine triphosphate production (ATPmax) was measured in vivo by 31P magnetic resonance spectroscopy. Leg extension power was measured with a Keiser press system, and VO2 peak was determined using a standardized cardiopulmonary exercise test. Gender-stratified multivariate linear regression models were adjusted for age, race, technician/site, adiposity, and physical activity with beta coefficients expressed per 1-SD increment in the independent variable. RESULTS: Max OXPHOS was associated with leg power for both women (ß = 0.12 Watts/kg, p < .001) and men (ß = 0.11 Watts/kg, p < .050). ATPmax was associated with leg power for men (ß = 0.09 Watts/kg, p < .05) but was not significant for women (ß = 0.03 Watts/kg, p = .11). Max OXPHOS and ATPmax were associated with VO2 peak in women and men (Max OXPHOS, ß women = 1.03 mL/kg/min, ß men = 1.32 mL/kg/min; ATPmax ß women = 0.87 mL/kg/min, ß men = 1.50 mL/kg/min; all p < .001). CONCLUSIONS: Higher muscle mitochondrial energetics measures were associated with both better cardiorespiratory fitness and greater leg power in older adults. Muscle mitochondrial energetics explained a greater degree of variance in VO2 peak compared to leg power.

Development of a Novel Accelerometry-Based Performance Fatigability Measure for Older Adults.

INTRODUCTION: Efforts to study performance fatigability have been limited because of measurement constrains. Accelerometry and advanced statistical methods may enable us to quantify performance fatigability more granularly via objective detection of performance decline. Thus, we developed the Pittsburgh Performance Fatigability Index (PPFI) using triaxial raw accelerations from wrist-worn accelerometer from two in-laboratory 400-m walks. METHODS: Sixty-three older adults from our cross-sectional study (mean age, 78 yr; 56% women; 88% White) completed fast-paced ( n = 59) and/or usual-paced 400-m walks ( n = 56) with valid accelerometer data. Participants wore ActiGraph GT3X+ accelerometers (The ActiGraph LLC, Pensacola, FL) on nondominant wrist during the walking task. Triaxial raw accelerations from accelerometers were used to compute PPFI, which quantifies percentage of area under the observed gait cadence-versus-time trajectory during a 400-m walk to a hypothetical area that would be produced if the participant sustained maximal cadence throughout the entire walk. RESULTS: Higher PPFI scores (higher score = greater fatigability) correlated with worse physical function, slower chair stands speed and gait speed, worse cardiorespiratory fitness and mobility, and lower leg peak power (| ρ | = 0.36-0.61 from fast-paced and | ρ | = 0.28-0.67 from usual-paced walks, all P < 0.05). PPFI scores from both walks remained associated with chair stands speed, gait speed, fitness, and mobility, after adjustment for sex, age, race, weight, height, and smoking status; PPFI scores from the fast-paced walk were associated with leg peak power. CONCLUSIONS: Our findings revealed that the objective PPFI is a sensitive measure of performance fatigability for older adults and can serve as a risk assessment tool or outcome measure in future studies and clinical practice.

Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women.

Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10-17), arthritis (GDF5 p = 4 × 10-13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.

Prevalence, Incidence, and Risk Factors for Overall, Physical, and Cognitive Independence Among Those From Exceptionally Long-Lived Families: The Long Life Family Study.

BACKGROUND: The Long Life Family Study (LLFS) enrolled families exhibiting exceptional longevity. The goal of this article was to determine the prevalence and predictors of remaining independent after 7 years in the oldest generation. METHODS: We examined 7-year change in physical (free of activities of daily living difficulty), cognitive (Mini-Mental State Examination score ≥ 24), and overall independence (physically/cognitively independent) in adults aged 90.3 ± 6.3 from LLFS's oldest generation. Potential predictors (n = 28) of remaining independent included demographics, diseases, biomarkers, anthropometrics, and physical and cognitive performance tasks and were determined using generalized estimating equations (α: p < .05). This was a discovery/exploratory analysis, so no multiple testing correction was employed and the results require independent replication. RESULTS: At baseline (n = 1442), 67.3%, 83.8%, and 79.7% were overall, physically, and cognitively independent, respectively. After 7 years, 66% died, 7.5% were lost to follow-up, and the prevalence of overall independence decreased to 59.1% in survivors (-8.2%, 95% confidence interval: -14.1%, 2.2%). Of those with baseline independence, 156/226 (69.0%) remained independent. Predictors of remaining physically independent included younger age, better Short Physical Performance Battery score and lung function, smaller waist circumference, and lower soluble receptor for advanced glycation end-product levels (p < .05). Predictors of remaining cognitively independent included no cancer history, better Digit Symbol Substitution Test performance, and higher body weight (p < .05). CONCLUSIONS: The prevalence of independence decreased by only 8.2% after 7 years, demonstrating the close correspondence between disability and mortality. Further, despite a mean baseline age of 90 years, a large proportion of survivors remained independent, suggesting this exceptional subgroup may harbor protective mechanisms.

Platelet bioenergetics correlate with muscle energetics and are altered in older adults.

BACKGROUND: Physical function decreases with age, and though bioenergetic alterations contribute to this decline, the mechanisms by which mitochondrial function changes with age remains unclear. This is partially because human mitochondrial studies require highly invasive procedures, such as muscle biopsies, to obtain live tissue with functional mitochondria. However, recent studies demonstrate that circulating blood cells are potentially informative in identifying systemic bioenergetic changes. Here, we hypothesize that human platelet bioenergetics reflect bioenergetics measured in muscle biopsies. METHODS & RESULTS: We demonstrate that maximal and ATP-linked respiratory rate measured in isolated platelets from older adults (86-93 years) correlates significantly with maximal respiration (r = 0.595; P = 0.003) measured by muscle biopsy respirometry and maximal ATP production (r = 0.643; P = 0.004) measured by 31P-MRS respectively, in the same individuals. Comparison of platelet bioenergetics in this aged cohort to platelets from younger adults (18-35 years) shows aged adults demonstrate lower basal and ATP-linked respiration. Platelets from older adults also show enhanced proton leak, which is likely due to increased protein levels of uncoupling protein 2, and correlates with increased gate speed in this cohort (r = 0.58; P = 0.0019). While no significant difference in glycolysis was observed in older adults compared to younger adults, platelet glycolytic rate correlated with fatigability (r = 0.44; P = 0.016). CONCLUSIONS: These data advance the mechanistic understanding of age-related changes in mitochondrial function. Further, they suggest that measuring platelet bioenergetics provides a potential supplement or surrogate for muscle biopsy measurement and may be a valuable tool to study mitochondrial involvement in age-related decline of physical function.

Are BMI and inflammatory markers independently associated with physical fatigability in old age?

BACKGROUND: Obesity and chronic low-grade inflammation have both been implicated in the onset of physical fatigue. However, few studies have investigated the independence of these associations in older community-dwelling populations. We therefore aimed to investigate the associations of body mass index (BMI) and inflammatory markers at age 60-64 with perceived physical fatigability at age 68 and to assess whether any such associations were independent of each other and potential confounding factors. A secondary aim was to investigate whether any association with BMI extended back into earlier adulthood. METHODS: Participants of the MRC National Survey of Health and Development (N = 1580) had BMI and levels of interleukin-6 (IL-6) and C-reactive protein (CRP) measured during clinical assessments at age 60-64. These were related to self-perceived physical fatigability assessed at age 68 using the Pittsburgh Fatigability Scale (PFS) (total score:0 (no physical fatigue)-50 (extreme physical fatigue)). RESUTS: Women had higher mean PFS scores than men (mean (SD): 16.0 (9.1) vs 13.2 (8.9), p < 0.01). In sex-adjusted models, BMI, CRP and IL-6 were each associated with PFS scores. When all three factors were included in the same model, BMI and IL-6 remained associated with PFS scores whereas CRP did not. After adjustment for a range of potential confounders, associations of BMI and IL-6 with PFS scores were still evident; fully adjusted differences in mean PFS score = 3.41 (95% CI: 0.59, 6.24) and 1.65 (0.46, 2.84) for underweight and obese participants when compared with normal weight and, 2.78 (1.65, 3.91) when comparing those with an IL-6 of 2.51-8.49 pg/mL with levels <1.50. CONCLUSIONS: BMI and inflammation may both be suitable targets for intervention to reduce the burden of physical fatigability in later life. Further, interventions that target both obesity and elevated levels of IL-6 are likely to be more effective than those focusing on only one.

Skeletal Muscle Mitochondrial Function and Fatigability in Older Adults.

BACKGROUND: Fatigability increases while the capacity for mitochondrial energy production tends to decrease significantly with age. Thus, diminished mitochondrial function may contribute to higher levels of fatigability in older adults. METHODS: The relationship between fatigability and skeletal muscle mitochondrial function was examined in 30 participants aged 78.5 ± 5.0 years (47% female, 93% white), with a body mass index of 25.9 ± 2.7 kg/m(2) and usual gait-speed of 1.2 ± 0.2 m/s. Fatigability was defined using rating of perceived exertion (6-20 point Borg scale) after a 5-minute treadmill walk at 0.72 m/s. Phosphocreatine recovery in the quadriceps was measured using (31)P magnetic resonance spectroscopy and images of the quadriceps were captured to calculate quadriceps volume. ATPmax (mM ATP/s) and oxidative capacity of the quadriceps (ATPmax·Quadriceps volume) were calculated. Peak aerobic capacity (VO2peak) was measured using a modified Balke protocol. RESULTS: ATPmax·Quadriceps volume was associated with VO2peak and was 162.61mM ATP·mL/s lower (p = .03) in those with high (rating of perceived exertion ≥10) versus low (rating of perceived exertion ≤9) fatigability. Participants with high fatigability required a significantly higher proportion of VO2peak to walk at 0.72 m/s compared with those with low fatigability (58.7 ± 19.4% vs 44.9 ± 13.2%, p < .05). After adjustment for age and sex, higher ATPmax was associated with lower odds of having high fatigability (odds ratio: 0.34, 95% CI: 0.11-1.01, p = .05). CONCLUSIONS: Lower capacity for oxidative phosphorylation in the quadriceps, perhaps by contributing to lower VO2peak, is associated with higher fatigability in older adults.