Spermidine-Activated Satellite Cells Are Associated with Hypoacetylation in ACVR2B and Smad3 Binding to Myogenic Genes in Mice

Abstract

Spermidine is an acetyltransferase inhibitor and a specific inducer of autophagy. Recently, spermidine is identified as a potential therapeutic agent for age-related muscle atrophy and inherited myopathies. However, the effect of spermidine on nonpathological skeletal muscle remains unclear. In this study, long-term spermidine administration in mice lowered the mean cross-sectional area of the gastrocnemius muscle and reduced the expression of myosin heavy chain isoforms in the muscle, which was associated with ubiquitination. Moreover, spermidine supplementation induced autophagy in satellite cells and enhanced satellite cell proliferation. ChIP assay revealed that spermidine repressed H3K56ac in the promoter of ACVR2B and lowered the binding affinity of Smad3 to the promoters of Myf5 and MyoD. Altogether, our results indicate that long-term administration of spermidine can activate satellite cells, as well as enhance autophagy, eventually resulting in muscle atrophy. In addition, H3K56ac and Smad3 emerged as key determinants of satellite cell activation.

Angiocrine polyamine production regulates adiposity

“…For spermidine treatment, wild-type C57BL/6J mice (purchased from Charles River) were fed with HFD and were treated with vehicle or spermidine (20 mg kg −1 ) from 6 to 12 weeks of age daily, excluding weekends. Of note, the spermidine supplementation strategy 20 mg kg −1 is within physiological ranges of spermidine supplementation 43,64 . All in vivo experiments of our study, including chow and HFD conditions, were performed without altering the normal presence of dietary polyamines.…”

Autophagy as a Therapeutic Target to Enhance Aged Muscle Regeneration

“…The positive benefits of spermidine in muscle tissues of mice and rats have been shown by mitigating age-related muscular atrophy as well as functional myopathies that originate from autophagy failure [157,158]. The autophagy-inducing effects of spermidine and rapamycin have also been detailed specifically within the muscle stem cell [1,159,160]. Satellite cells were isolated from aged mice and treated ex vivo with either rapamycin or spermidine and a dramatic increase in autophagy was measured by immunofluorescence of LC3 puncta.…”

Gynostemma pentaphyllum extract and Gypenoside L enhance skeletal muscle differentiation and mitochondrial metabolism by activating the PGC-1α pathway in C2C12 myotubes

“…Skeletal muscle is the most plentiful tissue in the human body. It supports physiological conditions [ 49 ] and possesses a remarkable ability for regeneration following severe cell damage resulting from exercise, injury, or disease [ 50 ]. As skeletal muscle-derived stem cells, satellite cells are the basal source for myogenesis and undergo differentiation into myocytes to repair myofibers following activation by muscle injury.…”