ABSTRACT
The branched-chain amino acid leucine stimulates muscle protein synthesis in part by directly activating the mTOR signaling pathway. Furthermore, leucine, if given in conjunction with resistance exercise, enhances the exercise-induced mTOR signaling and protein synthesis. Here we tested whether leucine can activate the mTOR anabolic signaling pathway in uremia and whether it can enhance work overload (WO)-induced signaling through this pathway. Chronic kidney disease (CKD) and control rats were studied after 7 days of surgically induced unilateral plantaris muscle WO and a single leucine or saline load. In the basal state, 4E-BP1 phosphorylation was modestly depressed in non-WO muscle of CKD rats, whereas rpS6 phosphorylation was nearly completely suppressed. After oral leucine mTOR, S6K1 and rpS6 phosphorylation increased similarly in both groups, whereas the phospho-4E-BP1 response was modestly attenuated in CKD. WO alone activated the mTOR signaling pathway in control and CKD rats. In WO CKD, muscle leucine augmented mTOR and 4E-BP1 phosphorylation, but its effect on S6K1 phosphorylation was attenuated. Taken together, this study has established that the chronic uremic state impairs basal signaling through the mTOR anabolic pathway, an abnormality that may contribute to muscle wasting. However, despite this abnormality, leucine can stimulate this signaling pathway in CKD, although its effectiveness is partially attenuated, including in skeletal muscle undergoing sustained WO. Thus, although there is some resistance to leucine in CKD, the data suggest a potential role for leucine-rich supplements in the management of uremic muscle wasting.
Subject(s)
Leucine/pharmacology , Muscle, Skeletal/drug effects , TOR Serine-Threonine Kinases/metabolism , Uremia/pathology , Animals , Chronic Disease , Drug Evaluation, Preclinical , Kidney/physiopathology , Kidney Failure, Chronic/complications , Kidney Failure, Chronic/metabolism , Kidney Failure, Chronic/pathology , Kidney Failure, Chronic/physiopathology , Male , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Muscular Diseases/etiology , Muscular Diseases/metabolism , Muscular Diseases/pathology , Muscular Diseases/physiopathology , Rats , Rats, Sprague-Dawley , Signal Transduction/drug effects , Uremia/etiology , Uremia/metabolism , Uremia/physiopathology , Wasting Syndrome/etiology , Wasting Syndrome/metabolism , Wasting Syndrome/pathology , Wasting Syndrome/physiopathology , Weight-Bearing/physiologyABSTRACT
Age related muscle loss, known as sarcopenia, is a major factor in disability, loss of mobility and quality of life in the elderly. There are many proposed mechanisms of age-related muscle loss that include the endocrine system. A variety of hormones regulate growth, development and metabolism throughout the lifespan. Hormone activity may change with age as a result of reduced hormone secretion or decreased tissue responsiveness. This review will focus on the complex interplay between the endocrine system, aging and skeletal muscle and will present possible benefits of therapeutic interventions for sarcopenia.