Muscle Energetics Research Articles

Sex differences in the association between skeletal muscle energetics and perceived physical fatigability: the Study of Muscle, Mobility and Aging (SOMMA).

Greater perceived physical fatigability and lower skeletal muscle energetics are bothpredictors 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 ex vivomeasures (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.

Leg cycling efficiency is unaltered in healthy aging regardless of sex or training status.

Muscular efficiency during exercise has been used to interrogate aspects of human muscle energetics, including mitochondrial coupling and biomechanical efficiencies. Typically, assessments of muscular efficiency have involved graded exercises. Results of previous studies have been interpreted to indicate a decline in exercise efficiency with aging owing to decreased mitochondrial function. However, discrepancies in variables such as exercise stage duration, cycling cadence, and treadmill walking mechanics may have affected interpretations of results. Furthermore, recent data from our lab examining the ATP to oxygen ratio (P:O) in mitochondrial preparations isolated from NIA mouse skeletal muscle showed no change with aging. Thus, we hypothesized that delta efficiency (Δ€) during steady-rate cycling exercise would not be altered in older healthy subjects compared with young counterparts regardless of biological sex or training status. Young (21-35 yr) and older (60-80 yr) men (n = 21) and women (n = 20) underwent continual, progressive leg cycle ergometer tests pedaling at 60 RPM for three stages (35, 60, 85 W) lasting 4 min. Δ€was calculated as: (Δ work accomplished/Δ energy expended). Overall, cycling efficiencies were not significantly different in older compared with young subjects. Similarly, trained subjects did not exhibit significantly different exercise efficiencies compared to untrained. Moreover, there were no differences between men and women. Hence, our results obtained on healthy young and older subjects are interpreted to mean that previous reports of decreased efficiency in older individuals were attributable to metabolic or biomechanical comorbidities, not aging per se.NEW & NOTEWORTHY Muscular power is reduced, but the efficiency of movement is unaltered in healthy aging.

Skeletal Muscle Energetics And Perceived Physical Fatigability Severity: The Study Of Muscle, Mobility And Aging

Skeletal Muscle Energetics And Perceived Physical Fatigability Severity: The Study Of Muscle, Mobility And Aging

Higher striatal dopamine is related with lower physical performance fatigability in community-dwelling older adults.

Fatigability in community-dwelling older adults is highly prevalent and disabling, but lacks a treatment. Greater nigrostriatal dopaminergic signaling can ameliorate performance fatigability in healthy young adults, but its role in community-dwelling older adults is not known. We hypothesized that higher nigrostriatal dopaminergic integrity would be associated with lower performance fatigability, independent of cardiopulmonary and musculoskeletal energetics and other health conditions. In 125 older adults participating in the Study of Muscle, Mobility and Aging, performance fatigability was measured as performance deterioration during a fast 400 meter walk (% slowing down from the 2nd to the 9th lap). Nigrostriatal DA integrity was measured using (+)-[11C] dihydrotetrabenazine (DTBZ) PET imaging. The binding signal was obtained separately for the subregions regulating sensorimotor (posterior putamen), reward (ventral striatum) and executive control processes (dorsal striatum). Multivariable linear regression models of performance fatigability (dependent variable) estimated the coefficients of dopamine integrity in striatal subregions, adjusted for demographics, comorbidities, and cognition. Models were further adjusted for skeletal muscle energetics (via biopsy) and cardiopulmonary fitness (via cardiopulmonary exercise testing). Higher [11C]-DTBZ binding in the posterior putamen was significantly associated with lower performance fatigability (demographic-adjusted standardized Beta = -1.08, 95% CI: -1.96, -0.20); results remained independent of adjustment for other covariates, including cardiopulmonary and musculoskeletal energetics. Associations with other striatal subregions were not significant. Dopaminergic integrity in the sensorimotor striatum may influence performance fatigability in older adults without clinically overt diseases, independent of other aging systems.

Abstract Tu093: Adeno-associated virus-mediated gene delivery of PERM1 enhances cardiac contractility and mitochondrial biogenesis in mice.

Heart failure remains the leading cause of death in the U.S., and 50% of patients with heart failure still die within 5 years after diagnosis. Mitochondrial impairment and contractile dysfunction are the hallmarks of heart failure with reduced ejection fraction (HFrEF). Yet, there is currently no therapeutic strategy targeting both mitochondria and muscle contractility. PERM1 is a striated-muscle-specific regulator of mitochondrial bioenergetics and is predominantly expressed in the heart and skeletal muscle. Our recent studies demonstrated that PERM1 is downregulated in human and mouse HFrEF hearts and that loss of PERM1 in mice leads to reduced contractility and energy reserve in the heart. However, it is largely unknown whether PERM1 positively regulates both muscle contractility and energetics in the heart. Here, we performed the gene delivery of Perm1 to the heart in C57BL6 wild-type mice (8-12 weeks old) through retro-orbital injection of the adenovirus-associated virus (AAV)9 vector carrying Perm1 (AAV-PERM1). The protein expression levels of PERM1 in the heart was increased by 3 fold as compared with control (mice injected with AAV9-GFP vectors), while there was no change in PERM1 expression in skeletal muscle (n=4/group). Strikingly, AAV-PERM1 mice exhibited a significant increase in ejection fraction (EF) and fractional shortening (FS) (AAV-GFP vs. AAV-PERM1: 0.93 vs. 1.43 and 0.92 vs. 1.64 in DEF and DFS, respectively, both p&lt;0.05 in t-test). In addition, we observed a subtle, yet significant increase in the ratio of the heart weight to tibial length in AAV-PERM1 mice (AAV-GFP vs. AAV-PERM1: 4.7 vs 5.97, p&lt;0.05 in t-test), suggestive of moderate cardiac hypertrophy development. Furthermore, PERM1 overexpression in the heart increased the mitochondrial copy number by 38% as compared to control AAV-GFP mice (p&lt;0.05 in t-test), concurrently with an upregulation of the mitochondrial bioenergetics master regulator PGC-1α (155% of control, p&lt;0.05 in t-test). Overall, these results showed that AAV-mediated PERM1 overexpression simultaneously enhances muscle contractility and mitochondrial biogenesis in the heart. This study further suggests that the gene delivery of PERM1 could be a potential therapeutic approach to treat HFrEF patients.

Skeletal Muscle Composition, Power, and Mitochondrial Energetics in Older Men and Women With Knee Osteoarthritis.

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.

Sex Differences in the Association between Skeletal Muscle Energetics and Perceived Physical Fatigability: The Study of Muscle, Mobility and Aging (SOMMA).

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.

Sourcebook update: using near-infrared spectroscopy to assess skeletal muscle oxygen uptake.

Monitoring the metabolic cost or oxygen consumption associated with rest and exercise is crucial to understanding the impact of disease or physical training on the health of individuals. Traditionally, measuring the skeletal muscle oxygen cost associated with exercise/muscle contractions can be rather expensive or invasive (i.e., muscle biopsies). More recently, specific protocols designed around the use of near-infrared spectroscopy (NIRS) have been shown to provide a quick, noninvasive easy-to-use tool to measure skeletal muscle oxygen consumption ([Formula: see text]). However, the data and results from NIRS devices are often misunderstood. Thus the primary purpose of this sourcebook update is to provide several experimental protocols students can utilize to improve their understanding of NIRS technology, learn how to analyze results from NIRS devices, and better understand how muscle contraction intensity and type (isometric, concentric, or eccentric) influence the oxygen cost of muscle contractions.NEW & NOTEWORTHY Compared to traditional methods, near-infrared spectroscopy (NIRS) provides a relatively cheap and easy-to-use noninvasive technique to measure skeletal muscle oxygen uptake following exercise. This laboratory not only enables students to learn about the basics of NIRS and muscle energetics but also addresses more complex questions regarding skeletal muscle physiology.

Muscle Mitochondrial Bioenergetic Capacities Are Associated With Multimorbidity Burden in Older Adults: The Study of Muscle, Mobility and Aging.

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. The Study of Muscle, Mobility and Aging (SOMMA) assessed ex vivo muscle mitochondrial energetics in 764 older adults (mean age = 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, N = 332; 1 condition, N = 299; 2 conditions, N = 98; or 3+ conditions, N = 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. 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 (POR = 1.32 [1.13, 1.54]) and separately with diabetes mellitus (OR = 1.62 [1.26, 2.09]), depressive symptoms (OR = 1.45 [1.04, 2.00]) and possibly chronic kidney disease (OR = 1.57 [0.98, 2.52]) but not significantly with other conditions (eg, cardiac arrhythmia, chronic obstructive pulmonary disease). 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.

Endurance training and hydroxyurea have synergistic effects on muscle function and energetics in sickle cell disease mice

Sickle cell disease (SCD) is an hemoglobinopathy resulting in the production of an abnormal Hb (HbS) which can polymerize in deoxygenated conditions, leading to the sickling of red blood cells (RBC). These alterations can decrease the oxygen-carrying capacity leading to impaired function and energetics of skeletal muscle. Any strategy which could reverse the corresponding defects could be of interest. In SCD, endurance training is known to improve multiples muscle properties which restores patient's exercise capacity but present reduced effects in anemic patients. Hydroxyurea (HU) can increase fetal hemoglobin production which can reduce anemia in patients. The present study was conducted to determine whether HU can improve the effects of endurance training to improve muscle function and energetics. Twenty SCD Townes mice have been trained for 8 weeks with (n = 11) or without (n = 9) HU. SCD mice muscle function and energetics were analyzed during a standardized rest-exercise-recovery protocol, using Phosphorus-31 Magnetic resonance spectroscopy (31P-MRS) and transcutaneous stimulation. The combination of training and HU specifically decreased fatigue index and PCr consumption while muscle oxidative capacity was improved. These results illustrate the potential synergistic effects of endurance training and HU on muscle function and energetics in sickle cell disease.

Association between dietary phosphate intake and skeletal muscle energetics in adults without cardiovascular disease.

Highly bioavailable inorganic phosphate (Pi) is present in large quantities in the typical Western diet and represents a large fraction of total phosphate intake. Dietary Pi excess induces exercise intolerance and skeletal muscle mitochondrial dysfunction in normal mice. However, the relevance of this to humans remains unknown. The study was conducted on 13 individuals without a history of cardiopulmonary disease (46% female, 15% Black participants) enrolled in the pilot-phase of the Dallas Heart and Mind Study. Total dietary phosphate was estimated from 24-h dietary recall (ASA24). Muscle ATP synthesis was measured at rest, and phosphocreatinine (PCr) dynamics was measured during plantar flexion exercise using 7-T 31P magnetic resonance (MR) spectroscopy in the calf muscle. Correlation was assessed between dietary phosphate intake normalized to total caloric intake, resting ATP synthesis, and PCr depletion during exercise. Higher dietary phosphate intake was associated with lower resting ATP synthesis (r = -0.62, P = 0.03), and with higher levels of PCr depletion during plantar flexion exercise relative to the resting period (r = -0.72; P = 0.004). These associations remain significant after adjustment for age and estimated glomerular filtration rate (both P < 0.05). High dietary phosphate intake was also associated with lower serum Klotho levels, and Klotho levels are in turn associated with PCr depletion and higher ADP accumulation post exercise. Our study suggests that higher dietary phosphate is associated with reduced skeletal muscle mitochondrial function at rest and exercise in humans providing new insight into potential mechanisms linking the Western diet to impaired energy metabolism.NEW & NOTEWORTHY This is the first translational research study directly demonstrating the adverse effects of dietary phosphate on muscle energy metabolism in humans. Importantly, our data show that dietary phosphate is associated with impaired muscle ATP synthesis at rest and during exercise, independent of age and renal function. This is a new biologic paradigm with significant clinical dietary implications.

Associations of accelerometry-measured and self-reported physical activity and sedentary behavior with skeletal muscle energetics: The Study of Muscle, Mobility and Aging (SOMMA)

BackgroundSkeletal 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. MethodsAs part of the Study of Muscle, Mobility and Aging, enrolled older adults (n = 879), 810 (age = 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. ResultsEvery 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/s × 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. ConclusionMore 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.

The Association of Skeletal Muscle Energetics With Recurrent Falls in Older Adults Within the Study of Muscle, Mobility and Aging.

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. 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. 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. 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.

Disentangling the dynamic interplay between muscle damage and energetics in male boxers during a short training block.

Boxing is a combat sport linked to muscle damage (e.g., soreness, rising creatine kinase [CK]) and energetic biomarkers (e.g., urea, glucose). These factors have not, however, been examined dynamically in terms of day-to-day, lagged and reciprocal effects during normal training. This study investigated the dynamic interplay between muscle damage and energetics in male boxers during a short training block. Thirteen amateur boxers were monitored over 16 consecutive days during early-season training. The participants were assessed each morning for plasma CK, urea, glucose, and creatinine (days 1 and 16 only) concentrations, before self-reporting muscle soreness (1-10 scale). Within-person contemporaneous (lag-0) and temporal (lag-1) networks were estimated using multilevel vector autoregression. Muscle soreness, CK, urea, and glucose presented different trajectories with training, but with some heterogeneity reflecting within-person variances (47% to 78%). The contemporaneous network yielded a significant positive edge (or correlation) between CK and soreness (r = 0.44), along with negative CK-glucose and glucose-urea edges. More significant edges emerged in the temporal network, with soreness linked to CK (r = 0.19), glucose (r = -0.28) and urea (r = 0.22), whilst the CK-glucose edge sign switched. In summary, daily fluctuations in muscle damage and energetic activity, which presented in a normal physiological range, were highly variable among boxers during early-season training. Within-person networks indicated some interrelatedness between CK, soreness, urea, and glucose, although the nature and presence of these relationships were contingent on temporal ordering. These inconsistences reflect the pleiotropy of energetic biomarkers in training and recovery.

Kiosk 7R-TB-05 - Cardiac and Skeletal Muscle Energetics in Chronic Heart Failure and Iron Deficiency

Kiosk 7R-TB-05 - Cardiac and Skeletal Muscle Energetics in Chronic Heart Failure and Iron Deficiency

Skeletal Muscle Energetics Explain the Sex Disparity in Mobility Impairment in the Study of Muscle, Mobility and Aging.

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.

GENDER DIFFERENCES IN SKELETAL MUSCLE ENERGETICS EXPLAIN THE MOBILITY IMPAIRMENT DISPARITY IN SOMMA

Abstract An age-related decline in muscle mitochondrial energetics is known to contribute to the loss of muscle function in older adults. Women experience a higher prevalence of mobility impairment compared to men, but it is unknown whether gender-specific differences in muscle energetics underlie this disparity. In the Study of Muscle, Mobility and Aging (SOMMA), muscle energetics were characterized using in vivo 31-Phosphorus Magnetic Resonance Spectroscopy and High-Resolution Respirometry of the vastus lateralis. A Short Physical Performance Battery score ≤ 8 was used to define lower-extremity mobility impairment. In this analysis of 773 participants age 70-94, women had greater odds (OR=1.83, p=0.03) of mobility impairment compared to men, which was largely explained by significantly lower muscle energetics (Maximal OXPHOS in Women= 55.06 +/- 15.95; Men= 65.80 +/- 19.74; p&amp;lt;0.0001) using mediation modeling (adjusted OR=1.25, p=0.45). The mobility impairment disparity could be further explained by BMI, race, physical activity, and number of comorbidities (adjusted OR=0.98, p=0.96). However, none of these covariates, including age, fully explained gender differences in muscle mitochondrial energetics (e.g. Adjusted Maximal OXPHOS in Women= 56.5, 95%CI=54.8, 58.1; Men= 64.4, 95%CI=62.5, 66.2; p&amp;lt;0.0001). Notably, high BMI and low gait speed were associated with lower muscle energetics, though BMI slightly more so in women (ATPmax BMI/gender interaction, p= 0.02) than men, and age was only significantly negatively associated with muscle energetics in men (e.g. Maximal ETS capacity age/gender interaction, p=0.04). In conclusion, women had lower muscle mitochondrial energetics compared to men, which largely explained their greater odds of lower-extremity mobility impairment.

SKELETAL MUSCLE ENERGETICS ARE ASSOCIATED WITH PERFORMANCE FATIGABILITY

Abstract Performance fatigability manifests as insufficient energy to complete daily physical tasks and worsens with aging, exacerbating vulnerability to disability. Skeletal muscle energetics also declines with aging. Thus, we hypothesized muscle energetics may be an important contributor to performance fatigability. In the Study of Muscle, Mobility and Aging (SOMMA), participants completed a usual-paced 400m walk while wearing a wrist-worn ActiGraph, from which raw data were used to derive the Pittsburgh Performance Fatigability Index (PPFI, higher=more severe fatigability) that quantifies percent decline in the entire individual cadence-versus-time trajectory. Maximal oxidative phosphorylation (maxOXPHOS) in skeletal muscle mitochondria was quantified in vitro using high-resolution respirometry in permeabilized fiber bundles from vastus lateralis muscle biopsies. Maximal adenosine triphosphate production (ATPmax) was assessed in vivo by 31P magnetic resonance spectroscopy. We conducted separate tobit regressions to examine associations of maxOXPHOS and ATPmax with PPFI, adjusting for technician/site, age, sex, race, height, weight, and mins/day moderate-to-vigorous physical activity measured by ActiGraph in free-living, in N=795 participants with complete PPFI scores and &amp;gt;1 energetics measure (70-94 yrs, 58% women). Median PPFI scores were 1.4% [IQR: 0-2.9%]. After adjustment, each SD (18.4 pmol/(s*mg)) lower maxOXPHOS was associated with 0.55% (95% CI: 0.26, 0.85) higher PPFI scores, while each SD (0.2 mM/sec) lower ATPmax was associated with 0.54% (95% CI: 0.27, 0.81) higher PPFI scores. Our results indicate that lower skeletal muscle energetics were associated with more severe performance fatigability. This suggests that therapeutics targeting muscle energetics may thereby potentially mitigate fatigability and lessen susceptibility to disability among older adults.

MITOCHONDRIAL ENERGETICS AND PERCEIVED PHYSICAL FATIGABILITY SEVERITY IN OLDER ADULTS

Abstract It has been hypothesized that lower skeletal muscle energetics may contribute to onset of age-related perceived fatigability. Consistent with this idea, previous research found that maximal ATP production (ATPmax) was associated with higher perceived exertion (i.e., fatigability) measured in older adults with the Borg Scale at the end of a slow walking task. We extend this work to SOMMA examining skeletal muscle energetics (ATPmax and maximal complex I&amp;II supported oxidative phosphorylation [maxOXPHOS]) with perceived physical fatigability using the Pittsburgh Fatigability Scale (PFS, range 0-50, higher=greater). PFS captures fatigue perception anchored to activities of varying intensity and duration. We assessed ATPmax in vivo by 31P magnetic resonance spectroscopy following an acute knee extensor exercise bout. maxOXPHOS was quantified ex vivo in permeabilized fiber bundles by high-resolution spectroscopy. Participants (N=721 with PFS and ≥1 energetics measure) were aged 76.4±5.0 years, 56.7% women, 86.7% White. Lower ATPmax (r=-0.21) and maxOXPHOS (r=-0.29) correlated with higher PFS scores (both p&amp;lt;0.001). Linear regressions adjusted for age, sex, technician, and total daily accelerometry-derived physical activity revealed that each one SD lower ATPmax (0.15 mM/sec) was associated with 1.15 (95% CI: 0.50, 1.79) higher PFS scores; each one SD lower maxOXPHOS (18.5 pmol/(sec*mg)) was associated with 1.79 (95% CI: 1.14, 2.45) higher PFS scores. Impaired skeletal muscle energetics may be implicated in the etiologic pathway of age-related fatigability. Next steps will examine the longitudinal association between changes in skeletal muscle energetics and age-related fatigability.

FATIGABILITY, FITNESS, AND CHRONO-NUTRITION: RESULTS FROM THE STUDY OF MUSCLE, MOBILITY AND AGING (SOMMA)

Abstract The Study of Muscle, Mobility and Aging (SOMMA) is a new longitudinal cohort study conducted at the University of Pittsburgh and Wake Forest University School of Medicine, coordinated by the San Francisco Coordinating Center, with management of biological specimens by the Translational Research Institute at AdventHealth. SOMMA aims to provide the foundation for discoveries in the biology of human aging, mobility and other age-related phenotypes. SOMMA enrolled 879 older women and men; mean age 76.3±5.0 years (range 70-94); mean walking speed 1.04±0.20 m/s; 59.2% women, and 15.8% identify as other than Non-Hispanic White. Our symposium will introduce novel baseline SOMMA findings on key measures related to fatigability, fitness, and chrono-nutrition. First, Dr. Schumacher will share results on the association between perceived physical and mental fatigability and cognitive function. Next, to begin to decipher how skeletal muscle energetics impact aging phenotypes, Ms. Gay will examine the relation between skeletal muscle energetics (ATPmax and maximal complex I&amp;II supported oxidative phosphorylation [maxOXPHOS]) and age-related physical fatigability. Our next two presentations will focus on cardiorespiratory fitness (VO2peak) measured by gold standard treadmill cardiopulmonary exercise testing (CPET), which declines with age. Ms. Moffit will explore whether a usual-paced 400m walk can predict VO2peak, and Dr. Erickson will examine the association between CPET measured VO2peak and circadian functions derived from rest-activity-rhythms extracted from wrist-worn accelerometers. Lastly, Dr. Farsijani will explore chrono-nutrition behaviors and their association with muscle health (i.e., D3-creatine, leg power). Discussant, Dr. Jennifer Schrack will provide insight to SOMMA’s novel work.