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The effects of exercise training on the skeletal muscle (SKM) lipidome and mitochondrial function have not been thoroughly explored in individuals with Type 2 diabetes (T2D). We hypothesize that 10 wk of supervised endurance training improves SKM mitochondrial function and insulin sensitivity that are related to alterations in lipid signatures within SKM of T2D (males n = 8). We employed integrated multi-omics data analyses including ex vivo lipidomics (MS/MS-shotgun) and transcriptomics (RNA-Seq). From biopsies of SKM, tissue and primary myotubes mitochondrial respiration were quantified by high-resolution respirometry. We also performed hyperinsulinemic-euglycemic clamps and blood draws before and after the training. The lipidomics analysis revealed that endurance training (>95% compliance) increased monolysocardiolipin by 68.2% ( P ≤ 0.03), a putative marker of mitochondrial remodeling, and reduced total sphingomyelin by 44.8% ( P ≤ 0.05) and phosphatidylserine by 39.7% ( P ≤ 0.04) and tended to reduce ceramide lipid content by 19.8%. Endurance training also improved intrinsic mitochondrial respiration in SKM of T2D without alterations in mitochondrial DNA copy number or cardiolipin content. RNA-Seq revealed 71 transcripts in SKM of T2D that were differentially regulated. Insulin sensitivity was unaffected, and HbA1c levels moderately increased by 7.3% despite an improvement in cardiorespiratory fitness (V̇o2peak) following the training intervention. In summary, endurance training improves intrinsic and cell-autonomous SKM mitochondrial function and modifies lipid composition in men with T2D independently of alterations in insulin sensitivity and glycemic control.

Skeletal muscle is a highly plastic organ regulating various processes in the body. As such, loss of skeletal muscle underlies the increased morbidity and mortality risk that is associated with numerous conditions. However, no therapies are available to combat the loss of muscle mass during atrophic conditions, which is due in part to the incomplete understanding of the molecular networks altered by anabolic and catabolic stimuli. Thus, the current objective was to identify novel gene networks modulated by such stimuli. For this, total RNA from the tibialis anterior muscle of mice that were fasted overnight or fasted overnight and refed the next morning was subjected to microarray analysis. The refeeding stimulus altered the expression of genes associated with signal transduction. Specifically, expression of alpha arrestin domain containing 2 (Arrdc2) and alpha arrestin domain containing 3 (Arrdc3) was significantly lowered 70–85% by refeeding. Subsequent analysis showed that expression of these genes was also lowered 50–75% by mechanical overload, with the combination of nutrients and mechanical overload acting synergistically to lower Arrdc2 and Arrdc3 expression. On the converse, stimuli that suppress growth such as testosterone depletion or acute aerobic exercise increased Arrdc2 and Arrdc3 expression in skeletal muscle. While Arrdc2 and Arrdc3 exhibited divergent changes in expression following anabolic or catabolic stimuli, no other member of the Arrdc family of genes exhibited the consistent change in expression across the analyzed conditions. Thus, Arrdc2 and Arrdc3 are a novel set of genes that may be implicated in the regulation of skeletal muscle mass.

The metabolic stress placed on skeletal muscle by aerobic exercise promotes acute and long-term health benefits in part through changes in gene expression. However, the transducers that mediate altered gene expression signatures have not been completely elucidated. Regulated in development and DNA damage 1 (REDD1) is a stress-induced protein whose expression is transiently increased in skeletal muscle following acute aerobic exercise. However, the role of this induction remains unclear. Because REDD1 altered gene expression in other model systems, we sought to determine whether REDD1 induction following acute exercise altered the gene expression signature in muscle. To do this, wild-type and REDD1-null mice were randomized to remain sedentary or undergo a bout of acute treadmill exercise. Exercised mice recovered for 1, 3, or 6 h before euthanization. Acute exercise induced a transient increase in REDD1 protein expression within the plantaris only at 1 h postexercise, and the induction occurred in both cytosolic and nuclear fractions. At this time point, global changes in gene expression were surveyed using microarray. REDD1 induction was required for the exercise-induced change in expression of 24 genes. Validation by RT-PCR confirmed that the exercise-mediated changes in genes related to exercise capacity, muscle protein metabolism, neuromuscular junction remodeling, and Metformin action were negated in REDD1-null mice. Finally, the exercise-mediated induction of REDD1 was partially dependent upon glucocorticoid receptor activation. In all, these data show that REDD1 induction regulates the exercise-mediated change in a distinct set of genes within skeletal muscle.