Aerobic training increases mitochondrial respiratory capacity in human skeletal muscle stem cells from sedentary individuals

Abstract

The impact of aerobic training on human skeletal muscle cell (HSkMC) mitochondrial metabolism is a significant research gap, critical to understanding the mechanisms by which exercise augments skeletal muscle metabolism. We therefore assessed mitochondrial content and capacity in fully differentiated CD56+ HSkMCs from lean active (LA) and sedentary individuals with obesity (OS) at baseline, as well as lean/overweight sedentary individuals (LOS) at baseline and following an 18-day aerobic training intervention. Participants had in vivo skeletal muscle PCr recovery rate by 31P-MRS (mitochondrial oxidative kinetics) and cardiorespiratory fitness (VO2max) assessed at baseline. Biopsies of the vastus lateralis were performed for the isolation of skeletal muscle stem cells. LOS individuals repeated all assessments post-training. HSkMCs were evaluated for mitochondrial respiratory capacity by high resolution respirometry. Data were normalized to two indices of mitochondrial content (CS activity and OXPHOS protein expression) and a marker of total cell count (quantity of DNA).LA individuals had significantly higher VO2max than OS and LOS-Pre training; however, no differences were observed in skeletal muscle mitochondrial capacity, nor in carbohydrate- or fatty acid-supported HSkMC respiratory capacity. Aerobic training robustly increased in vivo skeletal muscle mitochondrial capacity of LOS individuals, as well as carbohydrate-supported HSkMC respiratory capacity. Indices of mitochondrial content and total cell count were similar among the groups and did not change with aerobic training.Our findings demonstrate that bioenergetic changes induced with aerobic training in skeletal muscle in vivo are retained in HSkMCs in vitro without impacting mitochondrial content, suggesting that training improves intrinsic skeletal muscle mitochondrial capacity.

Translating In Vitro Models of Exercise in Human Muscle Cells: A Mitocentric View

“…Given the dearth of evidence on the impact of resistance exercise on SkM mitochondrial quality and quantity in vivo and ex vivo , further study with longer training interventions, comparing aerobic to resistance exercise training, would be helpful to assess the impact of different modes and durations of exercise training on imprinting metabolic properties of HSkMCs. As mentioned previously, the metabolic phenotype of the donor, as captured by improvements in mitochondrial quality and epigenetic modifications on mitochondrial-related genes with exercise training in SkM, is retained in their HSkMCs (11,18,19,48), thus emphasizing the translatability of the in vitro model. Therefore, alternative models of exercise treatments in vitro can be considered to further our understanding of training-induced mitochondrial adaptations in HSkMCs.…”

“…Evidence suggests that SkM stem cells isolated from SkM biopsies can be imprinted with metabolic properties through epigenetic modifications resulting from exercise (11,(17)(18)(19), offering a unique opportunity to distinguish novel mechanisms linked with in vivo training-induced mitochondrial adaptations and providing a robust in vitro model of isolated HSkMCs (20) (Fig. panel A).…”

“…The Table provides an overview of participant characteristics, in vivo or in vitro exercise training protocol, origin of HSkMCs, and measures of mitochondrial quality and quantity in response to the exercise intervention. The majority of these studies focused on the transcriptional signature that chronic aerobic exercise training alters in HSkMCs (11,17,48,49) (Table ). One study demonstrated significant increases in glucose oxidation, quantified using radiolabeled 14 C-glucose in HSkMCs from middle-aged males with obesity, after 8 wk of aerobic exercise training at five sessions per week (17).…”

“…Respiratory capacity measurements of SkM fibers ex vivo (10) or of HSkMCs in vitro (11) often are normalized to measurements of mitochondria quantity (12). As such, training-induced changes are attributed to intrinsic shifts in SkM mitochondrial quality independent of mitochondrial quantity.…”

“…Evidence suggests that SkM stem cells isolated from SkM biopsies can be imprinted with metabolic properties through epigenetic modifications resulting from exercise (11,17–19), offering a unique opportunity to distinguish novel mechanisms linked with in vivo training-induced mitochondrial adaptations and providing a robust in vitro model of isolated HSkMCs (20) (Fig. panel A). An example of this is the discovery of NR4A3 , an exercise- and inactivity-responsive gene, by profiling the SkM transcriptome to exercise and inactivity from a number of published datasets.…”