HDAC4 Knockdown Alleviates Denervation-Induced Muscle Atrophy by Inhibiting Myogenin-Dependent Atrogene Activation

Abstract

Denervation can activate the catabolic pathway in skeletal muscle and lead to progressive skeletal muscle atrophy. At present, there is no effective treatment for muscle atrophy. Histone deacetylase 4 (HDAC4) has recently been found to be closely related to muscle atrophy, but the underlying mechanism of HDAC4 in denervation-induced muscle atrophy have not been described clearly yet. In this study, we found that the expression of HDAC4 increased significantly in denervated skeletal muscle. HDAC4 inhibition can effectively diminish denervation-induced muscle atrophy, reduce the expression of muscle specific E3 ubiquitin ligase (MuRF1 and MAFbx) and autophagy related proteins (Atg7, LC3B, PINK1 and BNIP3), inhibit the transformation of type I fibers to type II fibers, and enhance the expression of SIRT1 and PGC-1 α. Transcriptome sequencing and bioinformatics analysis was performed and suggested that HDAC4 may be involved in denervation-induced muscle atrophy by regulating the response to denervation involved in the regulation of muscle adaptation, cell division, cell cycle, apoptotic process, skeletal muscle atrophy, and cell differentiation. STRING analysis showed that HDAC4 may be involved in the process of muscle atrophy by directly regulating myogenin (MYOG), cell cycle inhibitor p21 (CDKN1A) and salt induced kinase 1 (SIK1). MYOG was significantly increased in denervated skeletal muscle, and MYOG inhibition could significantly alleviate denervation-induced muscle atrophy, accompanied by the decreased MuRF1 and MAFbx. MYOG overexpression could reduce the protective effect of HDAC4 inhibition on denervation-induced muscle atrophy, as evidenced by the decreased muscle mass and cross-sectional area of muscle fibers, and the increased mitophagy. Taken together, HDAC4 inhibition can alleviate denervation-induced muscle atrophy by reducing MYOG expression, and HDAC4 is also directly related to CDKN1A and SIK1 in skeletal muscle, which suggests that HDAC4 inhibitors may be a potential drug for the treatment of neurogenic muscle atrophy. These results not only enrich the molecular regulation mechanism of denervation-induced muscle atrophy, but also provide the experimental basis for HDAC4-MYOG axis as a new target for the prevention and treatment of muscular atrophy.

Colorectal Cancer Chemotherapy Drug Bevacizumab May Induce Muscle Atrophy Through CDKN1A and TIMP4

“…In addition to its role in the occurrence, progression and treatment of cancer, CDKN1A has also been proved to be related to muscle atrophy. Wenjing Ma et al found that CDKN1A was upregulated in denervated skeletal muscle (30). The increase of CDKN1A expression level can also be found in the muscle atrophy model induced by starvation (31).Similarly, the expression of CDKN1A increased in the model of muscle atrophy induced by hindlimb suspension, but decreased after reloading (32).…”

A Nutraceutical Product Based on a Mixture of Algae and Extra Virgin Olive Oils and Olive Leaf Extract Attenuates Sepsis-Induced Cardiovascular and Muscle Alterations in Rats

“…In addition to atrogin-1 and MuRF1 overexpression, an increase in muscle HDAC4 and myogenin has been recently reported in sepsis ( 76 ), and in other conditions that induce muscle atrophy such as neurological disease ( 77 ), disuse ( 78 ) and aging ( 53 ). Furthermore, HDAC4 inhibition is reported to decrease denervation-induced muscle atrophy through decreased expression of muscle specific E3 ubiquitin ligases atrogin-1 and MuRF1 and autophagy related proteins ( 79 ). In this regard, we have previously reported that the treatment with this nutraceutical was also able to prevent the activation of the HDAC4-myogenin axis and the skeletal muscle loss induced by aging in rats ( 53 ).…”

SKP-SC-EVs Mitigate Denervated Muscle Atrophy by Inhibiting Oxidative Stress and Inflammation and Improving Microcirculation

“…A significant increase in proteolytic activity can directly cause skeletal muscle atrophy. Previous studies have shown that skeletal muscle atrophy is accompanied by significant activation of the proteolytic UPS and ALS pathways [ 13 , 14 ]. Moreover, oxidative stress and inflammation can trigger proteolysis by activating the UPS and ALS pathways [ 66 ].…”

“…Muscle ring-finger 1 (MuRF1) and muscle atrophy F-box (MAFbx) are two muscle-specific ubiquitin E3 ligases that are most essential to the UPS. They are highly expressed in a variety of muscle atrophy models [ 13 , 14 , 15 , 16 ]. Autophagy-related proteins, PINK1, BNIP3, LC3B, and ATG7, are key effectors of the ALS and also play an important role in the process of muscle atrophy.…”