Journal Article Epublish
PubMed: 42312157 DOI: 10.1021/acsptsci.6c00124
Myostatin Inhibitory D‑Peptides Induce Skeletal Muscle Hypertrophy along with Alteration of Bioactive Sphingolipid Metabolism.
ACS Pharmacol Transl Sci 9(6):1544-1553
Authors: Katsuya Morito, Natsuki Nishikawa, Keisuke Hitachi, Rina Tamaki, Minori Nishikawa, Yoshio Hayashi, Kunihiro Tsuchida, Kentaro Takayama
Affiliations
- Laboratory of Environmental Biochemistry, Kyoto Pharmaceutical University, Yamashina, Kyoto 607-8414, Japan.
- Division for Therapies against Intractable Diseases, Center for Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan.
- Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
Abstract
Myostatin inhibition is well-known as a promising strategy to induce skeletal muscle hypertrophy. Midsized peptides are currently noted as a new modality in broad drug development. Our previous studies identified a series of myostatin inhibitory peptides, including the 16-mer D-peptide inhibitor MID-35. However, the detailed pharmacological analysis of muscle growth provided by intramuscularly injected MID-35 has not been investigated. Additionally, since sphingosine 1-phosphate (S1P), one of the bioactive sphingolipids, is involved in the regulation of muscle mass, it is vital to explore whether MID-35 treatment affects the S1P metabolism. Here, we analyzed alterations induced by MID-35 administration in the tibialis anterior muscles of young, adult, and aged mice. Muscle differentiation-related markers (Pax7/Myod1/Myog) and atrophy-related markers (Trim63/Fbxo32) were robustly increased and decreased, respectively, within 3 days, and muscle weight gain first appeared 14 days later; intriguingly, the hypertrophy was sustained for 12 weeks. An increase in centralized nuclei and Pax7-positive signals in MID-35-treated muscles corroborated muscle regeneration associated with muscle satellite cells (mSCs). Additionally, changes in the bioactive sphingolipid metabolism were observed. In young and adult mice, the amount of S1P was significantly increased on day 3, suggesting that S1P may assist in the activation of the mSCs. Meanwhile, aging affects S1P metabolism, resulting in no significant increase in the S1P level in aged mice. This basic study using MID-35 newly proposes the interaction between myostatin signaling and bioactive sphingolipid metabolism in the muscle hypertrophic reaction and would accelerate further mechanistic evaluation, including the maintenance of the hypertrophic state.
MeSH
Sphingolipids, Muscles, Hypertrophy, Aged, Myostatin, Muscle, Skeletal