Single-cell sequencing deconvolutes cellular responses to exercise in human skeletal muscle.

Skeletal muscle adaptations to exercise have been associated with a range of health-related benefits, but cell type-specific adaptations within the muscle are incompletely understood. Here we use single-cell sequencing to determine the effects of exercise on cellular composition and cell type-specific processes in human skeletal muscle before and after intense exercise. Fifteen clusters originating from six different cell populations were identified. Most cell populations remained quantitatively stable after exercise, but a large transcriptional response was observed in mesenchymal, endothelial, and myogenic cells, suggesting that these cells are specifically involved in skeletal muscle remodeling. We found three subpopulations of myogenic cells characterized by different maturation stages based on the expression of markers such as PAX7, MYOD1, TNNI1, and TNNI2. Exercise accelerated the trajectory of myogenic progenitor cells towards maturation by increasing the transcriptional features of fast- and slow-twitch muscle fibers. The transcriptional regulation of these contractile elements upon differentiation was validated in vitro on primary myoblast cells. The cell type-specific adaptive mechanisms induced by exercise presented here contribute to the understanding of the skeletal muscle adaptations triggered by physical activity and may ultimately have implications for physiological and pathological processes affecting skeletal muscle, such as sarcopenia, cachexia, and glucose homeostasis.

Interval-induced metabolic perturbation determines tissue fluid shifts into skeletal muscle.

Intense interval exercise has proven to be as effective as traditional endurance exercise in improving maximal oxygen uptake. Shared by these two exercise regimes is an acute reduction in plasma volume, which is a suggested stimulus behind exercise-induced increases in blood volume and maximal oxygen uptake. This study aimed to link exercise-induced metabolic perturbation with volume shifts into skeletal muscle tissue. Ten healthy subjects (mean age 33 ± 8 years, 5 males and 5 females) performed three 30 s all-out sprints on a cycle ergometer. Upon cessation of exercise magnetic resonance imaging, 31 Phosphorus magnetic resonance spectroscopy and blood samples were used to measure changes in muscle volume, intramuscular energy metabolites and plasma volume. Compared to pre-exercise, muscle volume increased from 1147.1 ± 35.6 ml to 1283.3 ± 11.0 ml 8 min post-exercise. At 30 min post-exercise, muscle volume was still higher than pre-exercise (1147.1 ± 35.6 vs. 1222.2 ± 6.8 ml). Plasma volume decreased by 16 ± 3% immediately post-exercise and recovered back to - 5 ± 6% after 30 min. Principal component analysis of exercise performance, muscle and plasma volume changes as well as changes in intramuscular energy metabolites showed generally strong correlations between metabolic and physiological variables. The strongest predictor for the volume shifts of muscle and plasma was the magnitude of glucose-6-phosphate accumulation post-exercise. Interval training leads to large metabolic and hemodynamic perturbations with accumulation of glucose-6-phosphate as a possible key event in the fluid flux between the vascular compartment and muscle tissue.

Circulatory factors associated with function and prognosis in patients with severe heart failure.

BACKGROUND: Multiple circulatory factors are increased in heart failure (HF). Many have been linked to cardiac and/or skeletal muscle tissue processes, which in turn might influence physical activity and/or capacity during HF. This study aimed to provide a better understanding of the mechanisms linking HF with the loss of peripheral function. METHODS AND RESULTS: Physical capacity measured by maximum oxygen uptake, myocardial function (measured by echocardiography), physical activity (measured by accelerometry), and mortality data was collected for patients with severe symptomatic heart failure an ejection fraction < 35% (n = 66) and controls (n = 28). Plasma circulatory factors were quantified using a multiplex immunoassay. Multivariate (orthogonal projections to latent structures discriminant analysis) and univariate analyses identified many factors that differed significantly between HF and control subjects, mainly involving biological functions related to cell growth and cell adhesion, extracellular matrix organization, angiogenesis, and inflammation. Then, using principal component analysis, links between circulatory factors and physical capacity, daily physical activity, and myocardial function were identified. A subset of ten biomarkers differentially expressed in patients with HF vs controls covaried with physical capacity, daily physical activity, and myocardial function; eight of these also carried prognostic value. These included established plasma biomarkers of HF, such as NT-proBNP and ST2 along with recently identified factors such as GDF15, IGFBP7, and TfR, as well as a new factor, galectin-4. CONCLUSIONS: These findings reinforce the importance of systemic circulatory factors linked to hemodynamic stress responses and inflammation in the pathogenesis and progress of HF disease. They also support established biomarkers for HF and suggest new plausible markers.