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

Research output: Contribution to journalArticle

61 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1649-1654
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number5
DOIs
StatePublished - Jan 31 2012

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Histone Deacetylases
Autophagy
Skeletal Muscle
Homeostasis
Muscular Diseases
Maintenance
Diet Therapy
Caloric Restriction
Sarcomeres
Poisons
Recycling
High Fat Diet
Weaning
Regeneration
Gene Expression
Muscles

Keywords

  • Autophagosome formation
  • Epigenetic regulation
  • Muscle disease
  • Muscle metabolism

ASJC Scopus subject areas

  • General

Cite this

Histone deacetylases 1 and 2 regulate autophagy flux and skeletal muscle homeostasis in mice. / Moresi, Viviana; Carrer, Michele; Grueter, Chad E.; Rifki, Oktay F.; Shelton, John M.; Richardson, James A.; Bassel-Duby, Rhonda; Olson, Eric N.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 5, 31.01.2012, p. 1649-1654.

Research output: Contribution to journalArticle

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