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Emerging evidence published over the past decade has highlighted the role of DNA methylation in skeletal muscle function and health, including as an epigenetic transducer of the adaptive response to exercise. In this review, we aim to synthesize the latest findings in this field to highlight: (1) the shifting understanding of the genomic localization of altered DNA methylation in response to acute and chronic aerobic and resistance exercise in skeletal muscle (e.g., promoter, gene bodies, enhancers, intergenic regions, un-annotated regions, and genome-wide methylation); (2) how these global/regional methylation changes relate to transcriptional activity following exercise; and (3) the factors (e.g., individual demographic or genetic features, dietary, training history, exercise parameters, local epigenetic characteristics, circulating hormones) demonstrated to alter both the pattern of DNA methylation after exercise, and the relationship between DNA methylation and gene expression. Finally, we discuss the changes in non-CpG methylation and 5-hydroxymethylation after exercise, as well as the importance of emerging single-cell analyses to future studies—areas of increasing focus in the field of epigenetics. We anticipate that this review will help generate a framework for clinicians and researchers to begin developing and testing exercise interventions designed to generate targeted changes in DNA methylation as part of a personalized exercise regimen. [ABSTRACT FROM AUTHOR]

Two-thirds of people with type 2 diabetes mellitus (T2DM) have or will develop chronic kidney disease (CKD), which is characterized by rapid renal decline that, together with superimposed T2DM-related metabolic sequelae, synergistically promotes early frailty and mobility deficits that increase the risk of mortality. Distinguishing the mechanisms linking renal decline to mobility deficits in CKD progression and/or increasing severity in T2DM is instrumental both in identifying those at high risk for functional decline and in formulating effective treatment strategies to prevent renal failure. While evidence suggests that skeletal muscle energetics may relate to the development of these comorbidities in advanced CKD, this has never been assessed across the spectrum of CKD progression, especially in T2DM-induced CKD. Here, using next-generation sequencing, we first report significant downregulation in transcriptional networks governing oxidative phosphorylation, coupled electron transport, electron transport chain (ETC) complex assembly, and mitochondrial organization in both middleand late-stage CKD in T2DM. Furthermore, muscle mitochondrial coupling is impaired as early as stage 3 CKD, with additional deficits in ETC respiration, enzymatic activity, and increased redox leak. Moreover, mitochondrial ETC function and coupling strongly relate to muscle performance and physical function. Our results indicate that T2DM-induced CKD progression impairs physical function, with implications for altered metabolic transcriptional networks and mitochondrial functional deficits as primary mechanistic factors early in CKD progression in T2DM. [ABSTRACT FROM AUTHOR]

Supplemental digital content is available in the text. Introduction: Prediabetes is a major risk factor for type 2 diabetes and cardiovascular diseases. Although resistance exercise (RE) is recommended for individuals with prediabetes, the effects of RE on postprandial glucose metabolism in this population are poorly understood. Therefore, the purpose of this study was to elucidate how RE affects postprandial glucose kinetics, insulin sensitivity, beta cell function, and glucose oxidation during the subsequent meal in sedentary men with obesity and prediabetes. Methods: We studied 10 sedentary men with obesity (body mass index, 33 ± 3 kg·m−2) and prediabetes by using a randomized, cross-over study design. After an overnight fast, participants completed either a single bout of whole-body RE (seven exercises, 3 sets of 10–12 repetitions at 80% one-repetition maximum each) or an equivalent period of rest. Participants subsequently completed a mixed meal test in conjunction with an intravenous [6,6-2H2]glucose infusion to determine basal and postprandial glucose rate of appearance (Ra) and disappearance (Rd) from plasma, insulin sensitivity, and the insulinogenic index (a measure of beta cell function). Skeletal muscle biopsies were obtained 90 min postmeal to evaluate pyruvate-supported and maximal mitochondrial respiration. Whole-body carbohydrate oxidation was assessed using indirect calorimetry. Results: RE significantly reduced the postprandial rise in glucose Ra and plasma glucose concentration. Postprandial insulin sensitivity was significantly greater after RE, whereas postprandial plasma insulin concentration was significantly reduced. RE had no effect on the insulinogenic index, postprandial pyruvate respiration, or carbohydrate oxidation. Conclusion/Interpretation: A single bout of RE has beneficial effects on postprandial glucose metabolism in men with obesity and prediabetes by increasing postprandial insulin sensitivity, reducing the postprandial rise in glucose Ra, and reducing postprandial plasma insulin concentration. [ABSTRACT FROM AUTHOR]

Objective: Proper exercise form is critical for the safety and efficacy of therapeutic exercise. This research examines if a novel smartphone application, designed to monitor and provide real-time corrections during resistance training, can reduce performance errors and elicit a motor learning response. Design: Forty-two participants aged 18 to 65 years were randomly assigned to treatment and control groups. Both groups were tested for the number of movement errors made during a 10-repetition set completed at baseline, immediately after, and 1 to 2 weeks after a single training session of knee extensions. The treatment group trained with real-time, smartphone-generated feedback, whereas the control subjects did not. Group performance (number of errors) was compared across test sets using a 2-factor mixed-model analysis of variance. Results: No differences were observed between groups for age, sex, or resistance training experience. There was a significant interaction between test set and group. The treatment group demonstrated fewer errors on posttests 1 and 2 compared with pretest (P < 0.05). There was no reduction in the number of errors on any posttest for control subjects. Conclusion: Smartphone apps, such as the one used in this study, may enhance patient supervision, safety, and exercise efficacy across rehabilitation settings. A single training session with the app promoted motor learning and improved exercise performance. [ABSTRACT FROM AUTHOR]

Background: Therapeutic exercise is a central component in the management of many common conditions. It is imperative, therefore, that clinicians monitor and correct patient performance to facilitate the use of proper form both in the clinic and during home exercise programs. Although clinicians are trained to prescribe exercise and analyze form, there are many subtleties that may be missed by relying on visual assessment. This study investigated the accuracy and precision of a novel, exercise-training smartphone application (app), running on an iPhone® (Apple, Cupertino, CA) 4 and using its LIS331DLH accelerometer to dynamically measure and record movement during exercise. Materials and Methods: The iPhone, running the app, was mounted to the movement arm of a Biodex™ isokinetic dynamometer System 4 (Biodex Corp., Shirley, NY). Angle and time measurements taken by the app were compared with the dynamometer (gold standard) while rotating at 30°/s, 60°/s, 90°/s, 120°/s, and 150°/s. Accuracy was assessed using limits of agreement and fast Fourier transform analyses. Precision was assessed using the coefficient of variation. Results: The mean difference between the app and the Biodex recordings was less than 1°/s for all test velocities. The coefficient of variation was less than 3% at velocities from 30°/s to 120°/s and less than 7% at 150°/s. Conclusions: The app was highly accurate and precise. The validation of apps designed for motion tracking is a vital prerequisite to clinical implementation. The app described in this article is clinically identical to the Biodex dynamometer in its ability to accurately and precisely read angular movement over time. [ABSTRACT FROM AUTHOR]

Facioscapulohumeral muscular dystrophy (FSHD) is caused by the aberrant expression of the double homeobox 4 (DUX4) gene. The FLExDUX4 mouse model carries an inverted human DUX4 transgene which has leaky DUX4 transgene expression at a very low level. No overt muscle pathology was reported before 16 weeks. The purpose of this study is to track and characterize the FLExDUX4 phenotypes for a longer period, up to one year old. In addition, transcriptomic changes in the muscles of 2-month-old mice were investigated using RNA-seq. The results showed that male FLExDUX4 mice developed more severe phenotypes and at a younger age in comparison to the female mice. These include lower body and muscle weight, and muscle weakness measured by grip strength measurements. Muscle pathological changes were observed at older ages, including fibrosis, decreased size of type IIa and IIx myofibers, and the development of aggregates containing TDP-43 in type IIb myofibers. Muscle transcriptomic data identified early molecular changes in biological pathways regulating circadian rhythm and adipogenesis. The study suggests a slow progressive change in molecular and muscle phenotypes in response to the low level of DUX4 expression in the FLExDUX4 mice. [ABSTRACT FROM AUTHOR]

Aims: To determine leg intermuscular (IMAT) and subcutaneous (SQAT) adipose tissue and their relationships with muscle performance and function in obese adults with and without type 2 diabetes and peripheral neuropathy (T2DMPN). Methods: Seventy-nine age-matched obese adults were studied, 13 T2DM, 54 T2DMPN, and 24 obese controls. Leg fat (%IMAT, %SQAT) volumes were quantified using MRI. Ankle plantar flexion (PF) torque and power were assessed with isokinetic dynamometry. Physical function was assessed with 9-item Physical Performance Test (PPT), 6-minute walk distance, single-limb balance, and time to ascend 10 stairs. One-way ANOVAs determined group differences, and multiple regression predicted PPT score from disease status, % IMAT, and PF power. Results: T2DMPN participants had 37% greater IMAT volumes and 15% lower SQAT volumes than controls (p =.01). T2DMPNand T2DMshowed reduced PF torque and power compared to controls. T2DMPNparticipants had lower PPT score, 6-minute walk, single-limb balance, and stair climbing than controls (all p < .05). %IMAT volume correlated inversely, and %SQAT correlated directly, with PPT. Leg %IMAT and disease status predicted 49% of PPT score. Conclusions: T2DMPN may represent a shift in adipose tissue accumulation from SQAT to IMAT depots, which is inversely associated with muscle performance and physical function. [ABSTRACT FROM AUTHOR]

Deficits in plasma membrane repair have been identified in dysferlinopathy and Duchenne Muscular Dystrophy, and contribute to progressive myopathy. Although Facioscapulohumeral Muscular Dystrophy (FSHD) shares clinicopathological features with these muscular dystrophies, it is unknown if FSHD is characterized by plasma membrane repair deficits. Therefore, we exposed immortalized human FSHD myoblasts, immortalized myoblasts from unaffected siblings, and myofibers from a murine model of FSHD (FLExDUX4) to focal, pulsed laser ablation of the sarcolemma. Repair kinetics and success were determined from the accumulation of intracellular FM1-43 dye post-injury. We subsequently treated FSHD myoblasts with a DUX4-targeting antisense oligonucleotide (AON) to reduce DUX4 expression, and with the antioxidant Trolox to determine the role of DUX4 expression and oxidative stress in membrane repair. Compared to unaffected myoblasts, FSHD myoblasts demonstrate poor repair and a greater percentage of cells that failed to repair, which was mitigated by AON and Trolox treatments. Similar repair deficits were identified in FLExDUX4 myofibers. This is the first study to identify plasma membrane repair deficits in myoblasts from individuals with FSHD, and in myofibers from a murine model of FSHD. Our results suggest that DUX4 expression and oxidative stress may be important targets for future membrane-repair therapies. [ABSTRACT FROM AUTHOR]

Weight loss and exercise are the cornerstones of therapy for patients with obesity and type 2 diabetes (T2D). However, successful compliance with therapy is difficult to achieve. We conducted an 8-month randomized, controlled trial in persons with obesity and T2D to determine the effect of intensive lifestyle therapy (ILT), delivered at a worksite setting, on body weight, cardiometabolic function, and cellular metabolic pathways. Subjects were assigned to Standard Care (SC; n=8, BMI:38±5, fasting blood glucose [FBG]:161±19 mg/dl, HbA1c:7.6±1.1%) or ILT (n=10, BMI:37±6, FBG:150±32 mg/dl, HbA1c:7.0±1.1%), which involved weekly diet-behavior therapy sessions and 4 d/wk of supervised resistance and endurance exercise training. Weight loss was greater in the ILT than SC group (17±7% vs. 1±2%, P<0.05). All cardiometabolic outcomes improved more in the ILT than SC group: i) insulin sensitivity (glucose disposal rate during a hyperinsulinemic-euglycemic clamp increased by 116±78% vs. 15±9%, P<0.05); ii) β-cell function (insulin secretion in response to an oral glucose load relative to insulin sensitivity increased by 194±205% vs. 12±20%, P<0.05); and iii) cardiorespiratory fitness (VO2 peak during cycle ergometer exercise increased by 28±22% vs. -2±15%, P<0.05). The most upregulated biological pathways enriched in differentially expressed genes (DEGs) in skeletal muscle, assessed by RNA-seq, after ILT involved mitochondrial function and sirtuin signaling pathways. Upstream regulators of these DEGs included NAD dependent deacetylase sirtuin-3 (SIRT3) and NAMPT (FDR<0.05). In addition, ILT increased muscle NAD content by 51±46% (P<0.05). FBG and HbA1c decreased to 108±31 mg/dl and to 6.1±0.9%, despite a 60% decrease in the use of diabetes medications after ILT, but did not change with SC. We conclude that marked diet-induced weight loss and exercise training can be achieved in a structured worksite setting and has profound therapeutic cardiometabolic effects in people with obesity and T2D. Disclosure: M. Yoshino: None. B. W. Patterson: None. S. Klein: Advisory Panel; Self; Altimmune, Merck & Co., Inc., Novo Nordisk Inc., ProSciento, Research Support; Self; Janssen Research & Development, LLC. J. Yoshino: None. A. J. Bittel: None. D. Bittel: None. D. Reeds: None. R. Stein: None. D. R. Sinacore: None. W. T. Cade: None. A. L. Okunade: None. Funding: American Egg Board; National Dairy Council (T32DK07296DK007120) [ABSTRACT FROM AUTHOR]

Barth syndrome (BTHS) is an ultra-rare, X-linked recessive disorder characterized by cardio-skeletal myopathy, exercise intolerance, and growth delay. Oxygen uptake during peak exercise (VO2peak) has been shown to be severely limited in individuals with BTHS however; the trajectory of VO2peak from childhood to young adulthood is unknown. The objective of this study was to describe VO2peak from childhood through young adulthood in BTHS. Methods and Materials: VO2peak over time was presented through cross-sectional (n = 33 participants) and a longitudinal analyses (n = 12 participants). Retrospective data were obtained through maximal exercise testing on a cycle ergometer from individuals with BTHS who were or are currently enrolled in a research study during July 2006-September 2017. Participants included in the cross-sectional analysis were divided into 3 groups for analysis: 1) children (n = 13), 2) adolescents (n = 8), and 3) young adults (n = 12). Participants in the longitudinal analysis had at least two exercise tests over a span of 2–9 years. Results: VO2peak relative to body weight (ml/kgBW/min), fat-free mass (FFM) and by percent of predicted VO2peak obtained were not significantly different between children, adolescents and young adults. VO2peak did not longitudinally change over a mean time of ~5 years in late adolescent and young adult participants with repeated tests. A model including both cardiac and skeletal muscle variables best predicted VO2peak. Conclusions: In conclusion, VO2peak relative to body weight and fat-free mass demonstrates short- and long-term stability from childhood to young adulthood in BTHS with some variability among individuals. [ABSTRACT FROM AUTHOR]