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 transduction pathways governing muscle protein metabolism, apoptosis, and autophagy in R6/2 mice, a well-characterized transgenic model of HD. R6/2 mice exhibited increased adiposity, elevated energy expenditure, and decreased body weight and lean mass without altered food intake. Severe skeletal muscle wasting accounted for a majority of the weight loss. Protein synthesis was unexpectedly increased 19% in gastrocnemius muscle, which was associated with overactivation of basal and refeeding-stimulated mammalian target of rapamycin (mTOR) signaling, elevated Akt expression and Ser(473) phosphorylation, and decreased AMPK Thr(172) phosphorylation. Moreover, mRNA abundance of atrogenes muscle 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 several caspase genes and genes involved in the extrinsic or intrinsic apoptotic pathway, caspase-3/7, -8, and -9 activity, protein abundance of caspase-3 and -9, Fas, and Fadd, and cytochrome c release were elevated. Protein expressions of LC3B-I and -II, beclin-I, and atg5 and -7 in muscle were upregulated. Thus, mutant huntingtin in skeletal muscle results in increased protein synthesis and mTOR signaling, which is countered by activation of the apoptotic and autophagic pathways, contributing to an overall catabolic phenotype and the severe muscle wasting.

• Authors: Pengxiang She, Zhiyou Zhang, Deanna Marchionini, William C Diaz, Thomas J Jetton, Scot R Kimball, Thomas C Vary, Charles H Lang, Christopher J Lynch
• Journal: American journal of physiology. Endocrinology and metabolism (Am J Physiol Endocrinol Metab) Vol. 301 Issue 1 Pg. E49-61 (Jul 2011) ISSN: 1522-1555 [Electronic] United States
• PMID: 21505144 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Topics

• Adiposity (genetics, physiology)
• Age Factors
• Animals
• Body Weight (genetics, physiology)
• Disease Models, Animal
• Energy Metabolism (genetics, physiology)
• Female
• Huntington Disease (complications, genetics, metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Inbred CBA
• Mice, Transgenic
• Muscle, Skeletal (metabolism, pathology)
• Muscular Atrophy (complications, genetics, metabolism, pathology)
• Signal Transduction (genetics)