Molecular characterization of skeletal muscle atrophy in the R6/2 mouse model of Huntington's disease

Pengxiang She, Zhiyou Zhang, Deanna Marchionini, William C. Diaz, Thomas J. Jetton, Scot R. Kimball, Thomas C. Vary, Charles H. Lang, Christopher J. Lynch

Research output: Contribution to journalArticle

40 Citations (Scopus)

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 Ser473 phosphorylation, and decreased AMPK Thr172 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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume301
Issue number1
DOIs
StatePublished - Jul 1 2011

Fingerprint

Muscular Atrophy
Huntington Disease
Skeletal Muscle
Muscles
Sirolimus
Caspase 3
Atrophy
Proteins
Phosphorylation
Caspase 7
Phenotype
Messenger RNA
AMP-Activated Protein Kinases
Caspase 9
Muscle Proteins
Autophagy
Adiposity
Proteasome Endopeptidase Complex
Caspases
Ubiquitin

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

Cite this

She, Pengxiang ; Zhang, Zhiyou ; Marchionini, Deanna ; Diaz, William C. ; Jetton, Thomas J. ; Kimball, Scot R. ; Vary, Thomas C. ; Lang, Charles H. ; Lynch, Christopher J. / Molecular characterization of skeletal muscle atrophy in the R6/2 mouse model of Huntington's disease. In: American Journal of Physiology - Endocrinology and Metabolism. 2011 ; Vol. 301, No. 1.
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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 Ser473 phosphorylation, and decreased AMPK Thr172 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.",
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Molecular characterization of skeletal muscle atrophy in the R6/2 mouse model of Huntington's disease. / She, Pengxiang; Zhang, Zhiyou; Marchionini, Deanna; Diaz, William C.; Jetton, Thomas J.; Kimball, Scot R.; Vary, Thomas C.; Lang, Charles H.; Lynch, Christopher J.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 301, No. 1, 01.07.2011.

Research output: Contribution to journalArticle

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