Histone deacetylase 4 is proective in amyotrophic lateral sclerosis and modulates the response to oxidative stress

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron degeneration, muscle atrophy and paralysis. Several factors account for the development of ALS, including accumulation of oxidative stress in skeletal muscle. A correlation between the histone deacetylase 4 (HDAC4) expression and the progression of the disease has been recently reported, but the role of HDAC4 in the disease is unknown. In this study we investigate HDAC4 role in ALS and in response to oxidative stress by deletion of HDAC4 in skeletal muscle in a mouse model of ALS, SOD1G93A mice. Lack of HDAC4 anticipates body weight loss in SOD1G93A HDAC4 mKO mice, inducing more pronounced muscle atrophy compared with SOD1G93A mice. To study the molecular mechanisms underlying HDAC4 function in response to a chronic denervation, such as in ALS, we cut the sciatic nerve of one limb of HDAC4 mKO mice and analyse muscles over time. HDAC4 mKO mice are resistant to muscle atrophy until two weeks following denervation, but at later time point muscles degenerate. Moreover, HDAC4 mKO muscles present ultrastructural defects in myofiber organization and higher levels of ROS in contralateral innervated muscle, while muscle architecture and the molecular responses to oxidative stress are blunted following denervation. From our results, we conclude that HDAC4 is important to maintain muscle mass and integrity upon oxidative stress, thus, the administration of HDAC4 inhibitors may be deleterious for ALS patients. Further studies are necessary to delineate the role of HDAC4 in skeletal muscle following chronic denervation.