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Exercise provides a robust physiological stimulus that evokes cross-talk among multiple tissues that when repeated regularly (i.e., training) improves physiological capacity, benefits numerous organ systems, and decreases the risk for premature mortality. However, a gap remains in identifying the detailed molecular signals induced by exercise that benefits health and prevents disease. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to address this gap and generate a molecular map of exercise. Preclinical and clinical studies will examine the systemic effects of endurance and resistance exercise across a range of ages and fitness levels by molecular probing of multiple tissues before and after acute and chronic exercise. From this multi-omic and bioinformatic analysis, a molecular map of exercise will be established. Altogether, MoTrPAC will provide a public database that is expected to enhance our understanding of the health benefits of exercise and to provide insight into how physical activity mitigates disease.

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, higher = 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 p  < .05; N  = 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. [ABSTRACT FROM AUTHOR]

BackgroundMitochondrial function declines with age; however, the relationship between adiposity and mitochondrial function among older adults is unclear. This study examined relationships between skeletal muscle mitochondrial content and electron transport chain complex 2 driven respiration with whole body and thigh composition, body fat distribution, and insulin sensitivity in older adults.Methods25 healthy, sedentary, weight-stable men (N = 13) and women (N = 12) >65 years of age, with a BMI range of 18-35 kg/m(2), participated in this study. Vastus lateralis biopsies were analyzed for citrate synthase (CS) activity and succinate mediated respiration of isolated mitochondria. Whole body and thigh composition were measured by DXA and CT. HOMA-IR was calculated using fasting glucose and insulin as an estimate of insulin sensitivity.ResultsSimilar to reports in middle-aged adults, skeletal muscle CS activity was negatively correlated with BMI (R = -0.43) in our cohort of older adults. Higher total and thigh adiposity were correlated with lower CS activity independent of BMI (R = -0.50 and -0.71 respectively). Maximal complex 2 driven mitochondrial respiration was negatively correlated with lower body adiposity in males (R = -0.66). In this cohort of non-diabetic older adults, both HOMA-IR and insulin were positively correlated with CS activity when controlling for BMI (R = 0.57 and 0.66 respectively).ConclusionsAdiposity and body composition are correlated with skeletal muscle mitochondrial content and electron transport chain function in healthy, sedentary, community dwelling, older adults. Specific relationships of mitochondrial bioenergetics with gender and insulin sensitivity are also apparent.Trial registrationClinicalTrials.gov identifier NCT01049698.

Obesity is linked to type 2 diabetes (T2D) and cardiovascular diseases; however, the underlying molecular mechanisms remain unclear. We aimed to identify obesity-associated molecular features that may contribute to obesity-related diseases. Using circulating monocytes from 1,264 Multi-Ethnic Study of Atherosclerosis (MESA) participants, we quantified the transcriptome and epigenome. We discovered that alterations in a network of coexpressed cholesterol metabolism genes are a signature feature of obesity and inflammatory stress. This network included 11 BMI-associated genes related to sterol uptake (↑LDLR, ↓MYLIP), synthesis (↑SCD, FADS1, HMGCS1, FDFT1, SQLE, CYP51A1, SC4MOL), and efflux (↓ABCA1, ABCG1), producing a molecular profile expected to increase intracellular cholesterol. Importantly, these alterations were associated with T2D and coronary artery calcium (CAC), independent from cardiometabolic factors, including serum lipid profiles. This network mediated the associations between obesity and T2D/CAC. Several genes in the network harbored C-phosphorus-G dinucleotides (e.g., ABCG1/cg06500161), which overlapped Encyclopedia of DNA Elements (ENCODE)-annotated regulatory regions and had methylation profiles that mediated the associations between BMI/inflammation and expression of their cognate genes. Taken together with several lines of previous experimental evidence, these data suggest that alterations of the cholesterol metabolism gene network represent a molecular link between obesity/inflammation and T2D/CAC.

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 31P 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. [ABSTRACT FROM AUTHOR]

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 VO2peak 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). VO2peak (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 VO2peak 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 VO2peak 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 VO2peak values. Bland–Altman plot and regression analyses indicated predicted VO2peak 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. [ABSTRACT FROM AUTHOR]

Cellular senescence is a biological aging process that is exacerbated by obesity and leads to inflammation and age- and obesogenic-driven chronic diseases including type 2 diabetes. Caloric restriction (CR) may improve metabolic function in part by reducing cellular senescence and the pro-inflammatory senescence-associated phenotype (SASP). We conducted an ancillary investigation of an 18-week randomized controlled trial (RCT) of CR (n  = 31) or Control (n  = 27) in 58 middle-aged/older adults (57.6 ± 5.8 years; 75% Women) with obesity and prediabetes. We measured mRNA expression of select senescence and apoptosis genes in blood CD3 + T cells (qRT-PCR) and a panel of 25 plasma SASP proteins (Luminex/multiplex; ELISA). Participants randomized to CR lost −10.8 ± 0.9 kg (−11.3% ± 5.4%) over 18 weeks compared with +0.5 ± 0.9 kg (+0.03% ± 3.5%) in Control group. T-cell expression of senescence biomarkers, p16INK4a and p21CIP1/WAF1, and apoptosis markers, BCL2L1 and BAK1, was not different between CR and Control groups in age, race, and sex-adjusted mixed models (p  > .05, all). Iterative principal axis factor analysis was used to develop composite SASP Factors, and the Factors comprising TNFRI, TNFRII, uPAR, MMP1, GDF15, OPN, Fas, and MPO were significantly altered with CR intervention (age, sex, race-adjusted mixed model time × treatment F  = 4.17, p  ≤ .05) and associated with the degree of weight loss (R 2 = 0.12, p  ≤ .05). Our study provides evidence from an RCT that specific circulating biomarkers of senescent cell burden are changed by CR in middle-aged and older adults with obesity and prediabetes. Future studies compare tissue and circulating levels of p16INK4a and pro-inflammatory SASP biomarkers in other populations, and interventions. [ABSTRACT FROM AUTHOR]