Histone deacetylase 4 is protective in ALS and modulates the response to oxidative stress

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron degeneration, muscle atrophy and weakness, eventually leading to muscle paralysis and death. Several factors account for the development of ALS, including accumulation of oxidative stress in skeletal muscle1. A positive correlation between the expression of the histone deacetylase 4 (HDAC4) and the progression of the disease has been recently reported in ALS patients, suggesting the use of HDAC4 inhibitors as a promising therapeutic approach for the treatment of this neurodegenerative disease2. HDAC4 in skeletal muscle plays a crucial role in the regulation of muscle mass and reinnervation following denervation3. However, the molecular pathways controlled by HDAC4 in ALS onset or progression, as well as in response to oxidativestress in skeletal muscle are not delineated yet. We investigated the role of HDAC4 in ALS by deleting HDAC4 in skeletal muscle of SOD1G93A mice, a mouse model of ALS. Lack of HDAC4 in skeletal muscle anticipated body weight loss and induced more pronounced muscle atrophy in late stage SOD1G93A HDAC4 mKO mice, compared with age-matched SOD1G93A mice, indicating a protective role of HDAC4 in ALS. 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 analyzed muscles over time. HDAC4 mKO mice did not undergo muscle atrophy for two weeks following denervation, but muscles degenerated at later time points. Moreover, contralateral innervated muscle of HDAC4 mKO mice presented ultrastructural defects in myofiber organization and higher levels of ROS, while alteration of sarcomeric architecture and the molecular responses to oxidative stress were blunted following denervation. From our results, we conclude that HDAC4 protects skeletal muscle in ALS and is important to maintain muscle integrity and oxidative stress response following denervation. Further studies are necessary to delineate the role of HDAC4 in skeletal muscle integrity and in response to chronic denervation.