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HDAC4 preserves skeletal muscle structure following long-term denervation by mediating distinct cellular responses.

ABSTRACT: BACKGROUND:Denervation triggers numerous molecular responses in skeletal muscle, including the activation of catabolic pathways and oxidative stress, leading to progressive muscle atrophy. Histone deacetylase 4 (HDAC4) mediates skeletal muscle response to denervation, suggesting the use of HDAC inhibitors as a therapeutic approach to neurogenic muscle atrophy. However, the effects of HDAC4 inhibition in skeletal muscle in response to long-term denervation have not been described yet. METHODS:To further study HDAC4 functions in response to denervation, we analyzed mutant mice in which HDAC4 is specifically deleted in skeletal muscle. RESULTS:After an initial phase of resistance to neurogenic muscle atrophy, skeletal muscle with a deletion of HDAC4 lost structural integrity after 4 weeks of denervation. Deletion of HDAC4 impaired the activation of the ubiquitin-proteasome system, delayed the autophagic response, and dampened the OS response in skeletal muscle. Inhibition of the ubiquitin-proteasome system or the autophagic response, if on the one hand, conferred resistance to neurogenic muscle atrophy; on the other hand, induced loss of muscle integrity and inflammation in mice lacking HDAC4 in skeletal muscle. Moreover, treatment with the antioxidant drug Trolox prevented loss of muscle integrity and inflammation in in mice lacking HDAC4 in skeletal muscle, despite the resistance to neurogenic muscle atrophy. CONCLUSIONS:These results reveal new functions of HDAC4 in mediating skeletal muscle response to denervation and lead us to propose the combined use of HDAC inhibitors and antioxidant drugs to treat neurogenic muscle atrophy.

SUBMITTER: Pigna E

PROVIDER: S-EPMC6389241 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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HDAC4 preserves skeletal muscle structure following long-term denervation by mediating distinct cellular responses.

Pigna Eva E Renzini Alessandra A Greco Emanuela E Simonazzi Elena E Fulle Stefania S Mancinelli Rosa R Moresi Viviana V Adamo Sergio S

Skeletal muscle 20180224 1

<h4>Background</h4>Denervation triggers numerous molecular responses in skeletal muscle, including the activation of catabolic pathways and oxidative stress, leading to progressive muscle atrophy. Histone deacetylase 4 (HDAC4) mediates skeletal muscle response to denervation, suggesting the use of HDAC inhibitors as a therapeutic approach to neurogenic muscle atrophy. However, the effects of HDAC4 inhibition in skeletal muscle in response to long-term denervation have not been described yet.<h4> ...[more]

PMID: 29477142

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Project description: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.

Project description:BACKGROUND Denervation-induced skeletal muscle atrophy results in significant biochemical and physiological changes potentially leading to devastating outcomes including increased mortality. Effective treatments for skeletal muscle diseases are currently not available. Muscle-specific miRNAs, such as miR-206, play an important role in the regulation of muscle regeneration. The aim of the present study was to examine the beneficial effects of miR-206 treatment during the early changes in skeletal muscle atrophy, and to study the underlying signaling pathways in a rat skeletal muscle atrophy model. MATERIAL AND METHODS The rat denervation-induced skeletal muscle atrophy model was established. miRNA-206 was overexpressed with or without TGF-β1 inhibitor in the rats. The mRNA and protein expression of HDAC4, TGF-β1, and Smad3 was determined by real-time PCR and western blot. The gastrocnemius muscle cross-sectional area and relative muscle mass were measured. MyoD1, TGF-β1, and Pax7 were determined by immunohistochemical staining. RESULTS After sciatic nerve surgical transection, basic muscle characteristics, such as relative muscle weight, deteriorated continuously during a 2-week period. Injection of miR-206 (30 μg/rat) attenuated morphological and physiological deterioration of muscle characteristics, prevented fibrosis effectively, and inhibited the expression of TGF-β1 and HDAC4 as assessed 2 weeks after denervation. Moreover, miR-206 treatment increased the number of differentiating (MyoD1+/Pax7+) satellite cells, thereby protecting denervated muscles from atrophy. Interestingly, the ability of miR-206 to govern HDAC4 expression and to attenuate muscle atrophy was weakened after pharmacological blockage of the TGF-b1/Smad3 axis. CONCLUSIONS TGF-β1/Smad3 signaling pathway is one of the crucial signaling pathways by which miR-206 counteracts skeletal muscle atrophy by affecting proliferation and differentiation of satellite cells. miR-206 may be a potential target for development of a new strategy for treatment of patients with early denervation-induced skeletal muscle atrophy.

Project description:BackgroundSkeletal muscle atrophy is a pathological condition that contributes to morbidity in a variety of conditions including denervation, cachexia, and aging. Muscle atrophy is characterized as decreased muscle fiber cross-sectional area and protein content due, in part, to the proteolytic activities of two muscle-specific E3 ubiquitin ligases: muscle RING-finger 1 (MuRF1) and muscle atrophy F-box (MAFbx or Atrogin-1). The nuclear factor-kappa B (NF-κB) pathway has emerged as a critical signaling network in skeletal muscle atrophy and has become a prime therapeutic target for the treatment of muscle diseases. Unfortunately, none of the NF-κB targeting drugs are currently being used to treat these diseases, likely because of our limited knowledge and specificity, for muscle biology and disease. The cellular inhibitor of apoptosis 1 (cIAP1) protein is a positive regulator of tumor necrosis factor alpha (TNFα)-mediated classical NF-κB signaling, and cIAP1 loss has been shown to enhance muscle regeneration during acute and chronic injury.MethodsSciatic nerve transection in wild-type, cIAP1-null and Smac mimetic compound (SMC)-treated mice was performed to investigate the role of cIAP1 in denervation-induced atrophy. Genetic in vitro models of C2C12 myoblasts and primary myoblasts were also used to examine the role of classical NF-κB activity in cIAP1-induced myotube atrophy.ResultsWe found that cIAP1 expression was upregulated in denervated muscles compared to non-denervated controls 14 days after denervation. Genetic and pharmacological loss of cIAP1 attenuated denervation-induced muscle atrophy and overexpression of cIAP1 in myotubes was sufficient to induce atrophy. The induction of myotube atrophy by cIAP1 was attenuated when the classical NF-κB signaling pathway was inhibited.ConclusionsThese results demonstrate the cIAP1 is an important mediator of NF-κB/MuRF1 signaling in skeletal muscle atrophy and is a promising therapeutic target for muscle wasting diseases.

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HDAC4 preserves skeletal muscle structure following long-term denervation by mediating distinct cellular responses.

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HDAC4 preserves skeletal muscle structure following long-term denervation by mediating distinct cellular responses.

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