Mechanisms of glucocorticoid-induced myopathy

Abstract

Glucocorticoid-induced muscle atrophy is characterized by fast-twitch or type II muscle fiber atrophy illustrated by decreased fiber cross-sectional area and reduced myofibrillar protein content. Muscle proteolysis, in particular through the ubiquitin-proteasome system (UPS), is considered to play a major role in the catabolic action of glucocorticoids. The stimulation by glucocorticoids of the UPS is mediated through the increased expression of several atrogenes ('genes involved in atrophy'), such as atrogin-1 and MuRF-1, two ubiquitin ligases involved in the targeting of protein to be degraded by the proteasome machinery. Glucocorticoids also exert an anti-anabolic action by blunting muscle protein synthesis. These changes in protein turnover may result from changes in the production of two growth factors which control muscle mass, namely IGF-I and myostatin respectively anabolic and catabolic toward the skeletal muscle. The decreased production of IGF-I as well as the increased production of myostatin have been both demonstrated to contribute to the muscle atrophy caused by glucocorticoids. At the molecular level, IGF-I antagonizes the catabolic action of glucocorticoids by inhibiting, through the PI3-kinase/Akt pathway, the activity of the transcription factor FOXO, a major switch for the stimulation of several atrogenes. These recent progress in the understanding of the glucocorticoidinduced muscle atrophy should allow to define new therapies aiming to minimize this myopathy. Promising new therapeutic approaches for treating glucocorticoid-induced muscle atrophy are also presented in this review.

Energy balance and fitness in adult survivors of childhood acute lymphoblastic leukemia

“…Glucocorticoid induced atrophy is characterized by decreased fiber crosssectional area and reduced myofibrillar protein content in fast-twitch glycolytic muscles. 53 Upper extremity muscles have a greater proportion of fast-twitch muscle fibers than the quadriceps. 54 Because sensorimotor function and balance are necessary for negotiating daily environments 55,56 and adequate hand strength is required for performance of fine motor tasks, 57 these findings are important.…”

Glucocorticoid regulation of the circadian clock modulates glucose homeostasis

“…In this model, glucocorticoids act as a synchronization signal to coordinate the circadian rhythm with energy balance. In contrast, significant breakdown of muscle protein is invoked only after prolonged fasting and other major physiological stressors that substantially alter the relatively modest circadian fluctuations in energy needs and glucocorticoid levels (49,50). Therefore, linkage of muscle wasting to circadian cycling might be disadvantageous.…”

Corticosteroid effects on ventilator-induced diaphragm dysfunction in anesthetized rats depend on the dose administered

“…Corticosteroids are known to decrease muscle synthesis and to accelerate protein degradation [4]. In vivo administration of corticosteroids to animals has been shown to stimulate the different proteolytic systems [22-26].…”

“…Glucocorticoids have been shown to cause mainly atrophy of fast-twitch type II muscle fibers with less or no impact on type I fibers [3]. In skeletal muscle, glucocorticoids decrease the rate of muscle protein synthesis and increase the rate of muscle proteolysis [4]. The stimulatory effect of corticosteroids on muscle proteolysis results from the activation of the proteolytic systems such as the ubiquitin-proteasome system (UPS), the lysosomal system, the calcium-dependent calpain system and the caspase-3 system [5,6].…”