Mechanisms and mediators that are associated with catabolic conditions to impair satellite cell function: role of glucocorticoids

Abstract

Chronic Kidney Disease (CKD) and Diabetes Mellitus (DM) have become epidemic diseases characterized by metabolic abnormalities and associated with cardiovascular and kidney complications. These catabolic conditions accelerate muscle protein degradation by activating caspase-3 and the ubiquitin-proteasome system (UPS). Several studies have shown that accumulation of the 14kD actin fragment in muscles of animals with accelerated protein degradation is due to catabolic conditions as such DM, CKD, acidosis, angiotensin II and insulin resistance. A type of "stem cell" in muscle is known as the satellite cell. After muscle injury, such as resistance exercise, satellite cells are activated and express the MyoD and myogenin transcription factors, leading to satellite cell proliferation and differentiation. In CKD, muscles of mice show decreased expression of MyoD, myogenin, and embryonic myosin heavy-chain protein (eMyHC) mRNAs, implying that loss of muscle mass is related to defects in the functions of satellite cells. An excess of glucocorticoids frequently accompanies catabolic conditions. This is relevant because glucocorticoids can suppress protein synthesis and raise protein degradation in muscle, contributing to muscle wasting. We hypothesize that mice with CKD or diabetes will have increased production of glucocorticoids leading to overexpression of myostatin in muscle. Synergistically, glucocorticoids and myostatin will stimulate the degradation of MyoD and this in turn, will suppress satellite cell function, ultimately leading to muscle atrophy. (AU)