HDACs in Skeletal Muscle Remodeling and Neuromuscular Disease

Bryan J. Simmons, Todd J. Cohen, Richard Bedlack, and Tso-Pang Yao

Contents

1 Skeletal Muscles Are Heterogeneous in Contractile and Metabolic Properties 80

2 Specification of Myofibers 81

3 Calcium Signaling and Activity-Dependent Muscle Remodeling 81

4 Class IIa Histone Deacetylases Are Potent Regulators of MEF2 83

5 Class IIa HDACs Are Signal-Responsive Deacetylases 85

6 Class IIa HDAC in Neural Activity-Dependent Muscle Remodeling 86

7 HDACs in Fiber Type Specification 87

8 HDACs in Synaptic Gene Expression 88

9 HDACs in Muscle Fiber Size Control and Atrophy 90

10 Complex Regulation of HDAC4 in Skeletal Muscle 90

11 HDACs in Skeletal Muscle Regeneration 91

12 Other Signaling Pathways in Skeletal Muscle Remodeling 93

13 HDAC4 and Amyotrophic Lateral Sclerosis 94

14 Class IIa HDACs as Therapeutic Targets 95

15 Concluding Remark 96

References 97

Abstract Skeletal muscle is made of heterogeneous myofibers with different contractile and metabolic properties. The diverse functionality of myofibers enables skeletal muscle to carry out different tasks from maintaining body posture to performing active movements. In addition to motility, skeletal muscle, which constitutes 40% of body mass, is also a key target of insulin action and performs an essential function in glucose metabolism. Adult skeletal muscle is a highly adaptive organ system and can undergo specific changes in contractile and metabolic properties to meet different functional demands. This plasticity of myofibers reflects a highly

Department of Pharmacology and Cancer Biology, Duke University, C325 LSRC, DUMC, BOX 3813, Durham, NC 27710, USA e-mail: [email protected]

T.-P. Yao and E. Seto (eds.), Histone Deacetylases: the Biology and Clinical Implication, 79 Handbook of Experimental Pharmacology 206, DOI 10.1007/978-3-642-21631-2_5, © Springer-Verlag Berlin Heidelberg 2011

coordinated change in gene expression program that is controlled by neural activity. The capacity for on-demand remodeling confers skeletal muscle the remarkable adaptability important for animal survival; its dysregulation, however, could contribute to muscle and metabolic diseases. How neural activity dictates transcriptional programming to modify muscle functionality and diversity is a fundamental issue. Recent studies have identified members of class IIa HDACs as important effectors in both physiological and pathological muscle remodeling. By way of modifying myofiber properties, pharmacological manipulation of IIa HDACs activity could have potential therapeutic utility in the treatment of muscle disorders.

Keywords Amyotrophic lateral sclerosis • HDAC • HDAC inhibitor • HDAC4 • Muscle atrophy • Muscle remodeling

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