Transthyretin Regulates Skeletal Muscle Stem Cell Proliferation and Skeletal Muscle Regeneration
YANG Qianni1, HAN Wanhong1, ZHANG Qianying1, HAN Chunmiao1, GAO Qing1, LI Hu1,2, ZHANG Yong1,2*, ZHU Dahai1,2*
Primary function of TTR (transthyretin) is to transport thyroxine and vitamin A. The ttr gene is predominantly expressed in the liver and is also expressed in choroid plexus and skeletal muscle. Previous studies have mainly focused on TTR functions in the brain and heart. The role of TTR in skeletal muscle is not well under stood. To investigate TTR function in regulating skeletal muscle development and regeneration, ttr KO (knockout) mice were generated in this study. There was no overt difference in body weight and skeletal muscle mass between ttr KO and WT (wild type) littermates. However, the ttr KO mice had poor skeletal muscle performance, as evi denced by smaller running exhaustion distance and weaker forelimb grip strength than that of WT littermates, sug gesting that TTR played important roles for physiological function of skeletal muscle. To explore the role of TTR in regulating skeletal muscle regeneration, the TA (tibialis anterior) muscle of ttr KO and WT mice were injured by CTX (cardiotoxin) and the regeneration was evaluated by quantifying size of regenerating myofibers. The data showed that the size of regenerating myofibers was significantly smaller in ttr KO mice than that of WT littermates, indicating that TTR played a role in regulating skeletal muscle regeneration. The number of Pax7-positive cells in the cryosection of the regenerated TA muscle from ttr KO mice was significantly reduced compared to that of WT mice, suggesting that TTR might implicate skeletal muscle regeneration by regulating muscle stem cell prolifera tion. Furthermore, EdU incorporation assay demonstrated that the proliferation of muscle stem cells FACS-sorted from ttr KO mice (Pax7-nGFP;ttr−/−) was slower than that of WT mice (Pax7-nGFP;ttr+/+). Collectively, this study reveals that TTR regulates skeletal muscle strength, exercise performance, muscle stem cell proliferation and skel etal muscle regeneration.
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