HDACs in Muscle Fiber Size Control and Atrophy

Chronically reduced neural activities associated with neuromuscular disease, aging and denervation can cause muscle atrophy, a condition characterized by excessive reduction in muscle size and strength. In neuromuscular diseases, such as amyo-trophic lateral sclerosis (ALS), motor neuron dysfunction leads to severe muscle atrophy in both diaphragm and limb muscles, contributing to breathing and mobility problems, and eventual death. The muscle atrophy program employs two ubiquitin E3 ligases, atrogin-1/MAFbx and MURF1, which are thought to promote muscle structural protein degradation by proteasomes (Bodine et al. 2001). In atrophic muscle arising from various dysfunctions such as denervation and immobilization, both atrogin-1 and MURF1 are transcriptionally induced. Genetic ablation of either atrogin1 or MURF1 partially spares muscle from atrophy (Bodine et al. 2001; Gomes et al. 2001). Recent data reveal that HDAC4 and HDAC5 induced in denervated muscle positively stimulates MURF1 transcription, thereby promoting muscle atrophy. Consistent with these data, inactivation of HDAC4 and HDAC5 by genetic ablation or specific siRNA spares denervated muscle from undergoing atrophy (Moresi et al. 2010). How HDAC4 regulates atrophy and MURF1 transcription is not known but it seems to involve the Dach2-myogenin transcriptional axis, which is also responsible for denervation-dependent synaptic gene induction (Cohen et al. 2007). However, as myogenin knockout mice are only partially resistant to denerva-tion-induced atrophy, additional HDAC4-dependent signaling pathways must participate in muscle atrophy. Interestingly, the HDAC4-dependent muscle atrophy appears to be independent of MEF2 activity, suggesting a complete independent HDAC4 target in the skeletal muscle (TJC, MCC, TPY, unpublished observation).

Sarcopenia is another form of muscle atrophy commonly associated with aging. Interestingly, in a gene expression study that compares muscle from young and old individuals, HDAC4 is one of the genes that are elevated in older individuals, possibly reflecting their reduced physical activity (Welle et al. 2003). If this induction of HDAC4 also contributes to sarcopenia, targeted inhibition of HDAC4 could have an important clinical utility in the geriatric population.

0 0

Post a comment