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

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.autophagosome formation | muscle disease | muscle metabolism | epigenetic regulation C ellular homeostasis is maintained by a balance between protein biosynthesis and degradation. Macroautophagy (herein referred to as autophagy) is a catabolic pathway responsible for the degradation of various cellular constituents or deleterious cellular components. The process involves formation of vesicles, called autophagosomes, that capture and deliver proteins to lysosomes for degradation (1). The resulting breakdown products are recycled and used to support cellular metabolism (2). Genetic studies with mice mutant for genes involved in autophagy substantiated the importance of basal autophagy for organelle turnover and cellular homeostasis (3-11). Various stress conditions, such as fasting, exercise, hypoxia, oxidative stress, and pathogen infection, trigger autophagy as an adaptive response to normalize cellular metabolism (12, 13).Deregulation of autophagy has been implicated in cancer (14, 15), neurodegenerative disorders (4, 5, 10), and muscular diseases (16,17). Epigenetic factors have been implicated in regulating autophagy during various pathological conditions (12). Alteration of the acetylation status of histones or other proteins through histone deacetylases (HDACs) is a key mechanism that controls gene transcription and protein function. Removal of acetyl groups from histone tails by HDACs promotes transcriptional repression by allowing chromatin compaction (18). HDACs also modulate the activity of a variety of transcription factors and large macromolecular complexes involved in diverse cellular processes (19)....

HDAC1 activates FoxO and is both sufficient and required for skeletal muscle atrophy

“…HDAC1 and HDAC2 are generally thought of as global transcriptional repressors owing to their role in the deacetylation of histones, which limits accessibility to gene promoters. However, gene array analyses of skeletal muscle from HDAC1 and HDAC2 double-knockout mice show only modest changes in global gene expression when compared to muscles from control mice (Moresi et al, 2012). Based on this finding, the authors of that study concluded that the functions of HDAC1 and HDAC2 in skeletal muscle are, likely, more specific than global transcriptional repression.…”

Essential role for autophagy in life span extension

“…Thus, H4K16 acetylation by the histone acetyltransferase KAT8 stimulates the expression of lethal levels of autophagy-relevant gene products (23). Nonetheless, mice lacking histone deacetylases (HDACs) such as HDAC1, HDAC2, or HDAC6 have impaired autophagy (24,25). Whether Figure 1.…”

Role of autophagy in COPD skeletal muscle dysfunction

“…Muscle-specific deletion of both HDAC1 and HDAC2 results in partial perinatal lethality, and HDAC1/2 knockout mice that survive postnatally develop progressive myopathies characterized by abnormal muscle degeneration/regeneration and metabolism that were associated with autophagy blockade (48).…”