Molecular Characterization of Skeletal Muscle Atrophy in the R6/2 Mouse Model of Huntington's Disease

Abstract

Huntington's disease (HD), a neurodegenerative disorder caused by mutant huntingtin, is characterized by a catabolic phenotype. To determine the mechanisms underlying muscle wasting, we examined key signal pathways governing protein metabolism and cellular turnover in R6/2 mice, a well characterized transgenic model of HD. R6/2 exhibited increased adiposity, elevated energy expenditure, decreased body weight and lean mass. Protein synthesis was unexpectedly increased 19% in gastrocnemius muscle, which was associated with overactivation of basal and refeeding-stimulated mTOR signaling, elevated AKT expression and Ser473 phosphorylation, and decreased AMPK Thr172 phosphorylation. Moreover, muscle mRNA expression of atrogenes, ring finger 1 and atrophy F-box was markedly attenuated during fasting and refeeding, and the urinary excretion of 3-methylhistidine was decreased, arguing against a role for the ubiquitin proteasome-mediated proteolysis in the atrophy. In contrast, mRNA expression of genes involved in the extrinsic apoptotic pathway, caspase-3/7, −8 and −9 activity, protein expression of caspase-3 and −9, Fas, and Fadd, and cytochrome C release were elevated. Protein expression of LC3B-I and -II, beclin-I, atg5 and atg7 in muscle was up-regulated. Thus, an increase in apoptosis and autophagy appear to contribute to an overall catabolic phenotype and the severe muscle wasting.