Histone deacetylase inhibition improves metabolism and mitochondrial dynamics: A potential novel therapeutic strategy for sarcopenia coexisting with diabetes mellitus

Ting-Wei Lee; Han-Wen Liu; Yuan-Feng Lin; Ting-I Lee; Yu-Hsun Kao; Yi-Jen Chen

doi:10.1016/j.mehy.2021.110724

Histone deacetylase inhibition improves metabolism and mitochondrial dynamics: A potential novel therapeutic strategy for sarcopenia coexisting with diabetes mellitus

Med Hypotheses. 2021 Oct 30:158:110724. doi: 10.1016/j.mehy.2021.110724. Online ahead of print.

Authors

Ting-Wei Lee¹, Han-Wen Liu², Yuan-Feng Lin³, Ting-I Lee⁴, Yu-Hsun Kao⁵, Yi-Jen Chen⁶

Affiliations

¹ Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
² Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
³ Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
⁴ Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Department of General Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: aglee@tmu.edu.tw.
⁵ Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Taipei Heart Institute, Taipei Medical University, Taipei, Taiwan. Electronic address: yuhsunkao@tmu.edu.tw.
⁶ Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Cardiovascular Research Center, Wan Fan Hospital, Taipei Medical University, Taipei, Taiwan; Taipei Heart Institute, Taipei Medical University, Taipei, Taiwan.

PMID: 34753007
DOI: 10.1016/j.mehy.2021.110724

Abstract

Sarcopenia, the age-associated-fragility with loss of skeletal muscle mass and function, often coexists with type 2 diabetes (T2D) in older individuals. Derangement of muscle metabolism and mitochondrial dynamics is critical, particularly in high-energy-demand organs in patients with metabolic disorder. However, targeted therapies to halt or reverse the pathological progression of sarcopenia coexisting with T2D are unavailable. Studies have identified the pathological roles of class I histone deacetylases (HDACs) in both T2D and sarcopenia. In addition to their proinflammatory properties, HDACs are known to modify muscle metabolism and mitochondrial dynamics in both the development of sarcopenia and pathogenesis of diabetes. Proper quality control of mitochondrial dynamics through protein degradation and the synthesis of new proteins may improve skeletal muscle function in sarcopenia. Class I HDAC inhibitors improve energy metabolism and modulate autophagy-related genes in skeletal muscle. However, class IIa HDAC4 plays a protective role in preserving skeletal muscle structure following long-term denervation, and selective inhibition of class IIa HDAC activity had no impact on oxidative metabolism of muscle mitochondria. These findings suggest the vital role of class I HDAC modulation in bioenergetics and mitochondria quality control, and may lead to a novel therapeutic strategy targeting sarcopenia that coexists with T2D. HDAC inhibitors have been approved for clinical applications, and interventions targeting on HDACs may be promising for the treatment of sarcopenia.

Keywords: Histone deacetylase; Metabolism; Mitochondria dynamics; Sarcopenia; Type 2 diabetes.