The duration of glucocorticoid treatment alters the anabolic response to high-force muscle contractions.

Abstract

Glucocorticoids induce a myopathy that includes loss of muscle mass and strength. Resistance exercise may reverse the muscle loss because it induces an anabolic response characterized by increases in muscle protein synthesis and potentially suppressing protein breakdown. Whether resistance exercise induces an anabolic response in glucocorticoid myopathic muscle is unknown, which is a problem because long-term glucocorticoid exposure alters the expression of genes that may prevent an anabolic response by limiting activation of pathways such as the mechanistic target of rapamycin in complex 1 (mTORC1). The purpose of this study was to assess whether high-force contractions initiate an anabolic response in glucocorticoid myopathic muscle. The anabolic response was analyzed by treating female mice with dexamethasone (DEX) for 7 days or 15 days. After treatment, the left tibialis anterior muscle of all mice was contracted via electrical stimulation of the sciatic nerve. Muscles were harvested 4 h after contractions. Rates of muscle protein synthesis were estimated using the SUnSET method. After 7 days of treatment, high-force contractions increased protein synthesis and mTORC1 signaling in both groups. After 15 days of treatment, high-force contractions activated mTORC1 signaling equally in both groups, but protein synthesis was only increased in control mice. The failure to increase protein synthesis may be because baseline synthetic rates were elevated in DEX-treated mice. The LC3 II/I ratio marker of autophagy was decreased by contractions regardless of treatment duration. These data show duration of glucocorticoid treatment alters the anabolic response to high-force contractions.NEW & NOTEWORTHY Glucocorticoid myopathy is the most common, toxic, noninflammatory myopathy. Our work shows that high-force contractions increase protein synthesis in skeletal muscle following short-term glucocorticoid treatment. However, longer duration glucocorticoid treatment results in anabolic resistance to high-force contractions despite activation of the mechanistic target of rapamycin in complex 1 (mTORC1) signaling pathway. This work defines potential limits for high-force contractions to activate the processes that would restore lost muscle mass in glucocorticoid myopathic patients.