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Molecular Characterization of Skeletal Muscle Atrophy in the R6/2 Mouse Model of Huntington's Disease
Author(s) -
She Pengxiang,
Zhang Zhiyou,
Marchionini Deanna,
Jetton Thomas,
Lang Charles,
Lynch Christopher
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1059.7
Subject(s) - endocrinology , medicine , muscle atrophy , skeletal muscle , biology , protein kinase b , huntingtin , pi3k/akt/mtor pathway , autophagy , mtorc1 , ampk , wasting , protein degradation , atrophy , phosphorylation , huntington's disease , apoptosis , signal transduction , microbiology and biotechnology , protein kinase a , biochemistry , disease
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.