Abstract

Skeletal muscle atrophy, a debilitating condition often induced by muscle unloading (e.g., bed rest, microgravity), is characterized by the upregulation of the muscle-specific E3 ubiquitin ligases, ATROGIN-1/MAFbx and MuRF1, which target muscle proteins for degradation. Histone deacetylases (HDACs), particularly those of Class IIa (HDAC4 and HDAC5), are known transcriptional regulators implicated in muscle plasticity. This study investigates the specific role of Class IIa HDACs in regulating the expression of ATROGIN-1/MAFbx and MuRF1 in response to muscle unloading. Using a hindlimb suspension model in mice, we analyzed the expression levels of Class IIa HDACs and the E3 ligases. Our findings indicate that muscle unloading significantly increases the nuclear localization of Class IIa HDACs, correlating with a marked transcriptional upregulation of both ATROGIN-1/MAFbx and MuRF1. Furthermore, genetic manipulation or pharmacological inhibition of Class IIa HDACs was shown to attenuate the increase in E3 ligase expression, suggesting a direct regulatory link. These results establish Class IIa HDACs as critical mediators in the signaling cascade that links mechanical unloading to the activation of the ubiquitin-proteasome system, providing a novel therapeutic target for combating muscle wasting conditions.