AMP-activated protein kinase mediates myogenin expression and myogenesis via histone deacetylase 5.

Abstract

There is a global epidemic of obesity, and obesity is known to inhibit AMP-activated protein kinase (AMPK) activity and impairs myogenesis. Myogenin mediates the fusion of myoblasts into myotubes, a critical step in myogenesis. We observed that inhibition of AMPKα1 downregulates myogenin expression and myogenesis, but the underlying mechanisms are unclear. We postulated that AMPK regulates myogenin expression through phosphorlytion of histone deacetylase 5 (HDAC5). In C2C12 cells, HDAC5 knockdown increased while HDAC5 stablization by MC1568 reduced myogenin expression. Consistently, using luciferase assay, we observed that myogenin promoter activity was negatively regulated by HDAC5. Using RNA interference and primary myoblasts prepared from wild-type and AMPKα1 knockout mice, we further demonstrate that AMPKα1 regulates HDAC5 phosphorylation at Ser 259 and 498. Mutation of these two Ser to Ala in HDAC5 abolished the regulatory role of AMPKα1 on myogenin expression, clearly showing the necessity of these phosphorylation sites in mediating myogenin expression. In aggregate, these data show that AMPK inhibition downregulates myogenin transcription and myogenesis through phosphorylation of HDAC5, mediated mainly by AMPKα1. These data demonstrate that AMPK is a key molecular target for promoting myogenesis and muscular regeneration. Because drugs activating AMPK activity, such as metformin, are widely available, our finding has critical clinical implications to ensure proper muscle development and regeneration in obese subjects and under other pathophysiological conditions where AMPK activity is attenuated.

• Authors: Xing Fu, Jun-Xing Zhao, Junfang Liang, Mei-Jun Zhu, Marc Foretz, Benoit Viollet, Min Du
• Journal: American journal of physiology. Cell physiology (Am J Physiol Cell Physiol) Vol. 305 Issue 8 Pg. C887-95 (Oct 15 2013) ISSN: 1522-1563 [Electronic] United States
• PMID: 23926128 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• MC1568
• Myogenin
• Pyrroles
• RNA, Small Interfering
• AMPK alpha1 subunit, mouse
• AMP-Activated Protein Kinases
• Hdac5 protein, mouse
• Histone Deacetylases

Topics

• AMP-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Animals
• Cell Differentiation
• Cells, Cultured
• Histone Deacetylase Inhibitors (pharmacology)
• Histone Deacetylases (genetics, metabolism)
• Hydroxamic Acids (pharmacology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Muscle Development
• Muscle Fibers, Skeletal
• Muscle, Skeletal (metabolism, physiology)
• Myoblasts (metabolism)
• Myogenin (genetics, metabolism)
• Phosphorylation
• Promoter Regions, Genetic
• Pyrroles (pharmacology)
• RNA Interference
• RNA, Small Interfering