Histone deacetylases 1 and 2 regulate autophagy flux and skeletal muscle homeostasis in mice

Viviana Moresi; Michele Carrer; Chad E Grueter; Oktay F Rifki; John M Shelton; James A Richardson; Rhonda Bassel-Duby; Eric N Olson

doi:10.1073/pnas.1121159109

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Histone deacetylases 1 and 2 regulate autophagy flux and skeletal muscle homeostasis in mice

Journal article

Open access

Peer reviewed

Histone deacetylases 1 and 2 regulate autophagy flux and skeletal muscle homeostasis in mice

Viviana Moresi, Michele Carrer, Chad E Grueter, Oktay F Rifki, John M Shelton, James A Richardson, Rhonda Bassel-Duby and Eric N Olson

Proceedings of the National Academy of Sciences - PNAS, Vol.109(5), pp.1649-1654

01/31/2012

DOI: 10.1073/pnas.1121159109

PMCID: PMC3277131

PMID: 22307625

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Abstract

Maintenance of skeletal muscle structure and function requires efficient and precise metabolic control. Autophagy plays a key role in metabolic homeostasis of diverse tissues by recycling cellular constituents, particularly under conditions of caloric restriction, thereby normalizing cellular metabolism. Here we show that histone deacetylases (HDACs) 1 and 2 control skeletal muscle homeostasis and autophagy flux in mice. Skeletal muscle-specific deletion of both HDAC1 and HDAC2 results in perinatal lethality of a subset of mice, accompanied by mitochondrial abnormalities and sarcomere degeneration. Mutant mice that survive the first day of life develop a progressive myopathy characterized by muscle degeneration and regeneration, and abnormal metabolism resulting from a blockade to autophagy. HDAC1 and HDAC2 regulate skeletal muscle autophagy by mediating the induction of autophagic gene expression and the formation of autophagosomes, such that myofibers of mice lacking these HDACs accumulate toxic autophagic intermediates. Strikingly, feeding HDAC1/2 mutant mice a high-fat diet from the weaning age releases the block in autophagy and prevents myopathy in adult mice. These findings reveal an unprecedented and essential role for HDAC1 and HDAC2 in maintenance of skeletal muscle structure and function and show that, at least in some pathological conditions, myopathy may be mitigated by dietary modifications.

Biological Sciences

muscle metabolism

autophagosome formation

muscle disease

epigenetic regulation

Details

Title: Subtitle: Histone deacetylases 1 and 2 regulate autophagy flux and skeletal muscle homeostasis in mice
Creators: Viviana Moresi - Departments of
Michele Carrer - Departments of
Chad E Grueter - Departments of
Oktay F Rifki - Internal Medicine, and
John M Shelton - Internal Medicine, and
James A Richardson - Departments of
Rhonda Bassel-Duby - Departments of
Eric N Olson - Departments of
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.109(5), pp.1649-1654
DOI: 10.1073/pnas.1121159109
PMID: 22307625
PMCID: PMC3277131
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences
Language: English
Date published: 01/31/2012
Academic Unit: Cardiovascular Medicine; Craniofacial Anomalies Research Center; Internal Medicine
Record Identifier: 9984094627402771

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