HDAC4 Regulates Skeletal Muscle Regeneration via Soluble Factors

Abstract

Skeletal muscle possesses a high ability to regenerate after an insult or in pathological conditions, relying on satellite cells, the skeletal muscle stem cells. Satellite cell behavior is tightly regulated by the surrounding microenvironment, which provides multiple signals derived from local cells and systemic factors. Among epigenetic mechanisms, histone deacetylation has been proved to affect muscle regeneration. Indeed, pan-histone deacetylase inhibitors were found to improve muscle regeneration, while deletion of histone deacetylase 4 (HDAC4) in satellite cells inhibits their proliferation and differentiation, leading to compromised muscle regeneration. In this study, we delineated the HDAC4 function in adult skeletal muscle, following injury, by using a tissue-specific null mouse line. We showed that HDAC4 is crucial for skeletal muscle regeneration by mediating soluble factors that influence muscle-derived cell proliferation and differentiation. These findings add new biological functions to HDAC4 in skeletal muscle that need considering when administering histone deacetylase inhibitors.

HDAC11 is a novel regulator of fatty acid oxidative metabolism in skeletal muscle

“…The main role of HDAC4 in myogenesis has been extensively studied and is through direct repression of MEF2, the master regulator of slow fiber program [4, [28][29][30][31]. In addition, HDAC4 expression is upregulated upon muscle injury and it is essential for an appropriate muscle regeneration [32][33][34]. HDAC4 expression is also upregulated upon muscle denervation-induced atrophy [35] and its inhibition prevents muscle atrophy by decreasing activation of ubiquitin, proteasome, autophagy, and oxidative stress pathways [36] and by increasing the acetylation levels of MyHC, PGC-1a, and Hsc70, rescuing muscle atrophy, and inducing mitochondrial biogenesis [37].…”

Effects of aerobic and inspiratory training on skeletal muscle microRNA‐1 and downstream‐associated pathways in patients with heart failure

“…Increased levels of microRNA‐1 can be also involved in postnatal myoblast differentiation by suppressing HDAC4, a predicted target gene of this myomiR . HDACs are well known for regulating muscle proliferation, differentiation, and growth through the regulation of histone acetylation.…”

“…In particular, class IIa HDACs (HDACs 4, 5, 7, and 9) plays an important role in the maintenance of muscle mass and protein degradation during muscle wasting . The reduced levels of HDAC4 promote myoblast differentiation, while increased levels of HDAC4 enhances skeletal muscle atrophy . Chen et al .…”

p300 and cAMP response element‐binding protein‐binding protein in skeletal muscle homeostasis, contractile function, and survival

“…In general, protein lysine acetylation is controlled by balance between the addition of acetyl groups from acetyl coenzyme A to a lysine residue by lysine acetyltransferases and their removal by lysine deacetylases . While a large body of work has elucidated roles for deacetylases in skeletal muscle regulation, contributions of acetyltransferases to skeletal muscle physiology and function remain to be determined.…”