Abstract
BackgroundSkeletal muscle atrophy and fibrosis are pathological conditions that contribute to morbidity in numerous conditions including aging, cachexia, and denervation. Muscle atrophy is characterized as reduction of muscle fiber size and loss of muscle mass while muscle fibrosis is due to fibroblasts activation and excessive production of extracellular matrix. Purinergic receptor P2Y2 has been implicated in fibrosis. This study aims to elucidate the roles of P2Y2 in sleketal muscle atrophy and fibrosis.MethodsPrimary muscle fibroblasts were isolated from wild type and P2Y2 knockout (KO) mice and their proliferating and migrating abilities were assessed by CCK-8 and Transwell migration assays respectively. Fibroblasts were activated with TGF-β1 and assessed by western blot of myofibroblast markers including α-SMA, CTGF, and collagen I. Muscle atrophy and fibrosis were induced by transection of distal sciatic nerve and assessed using Masson staining.ResultsP2Y2 KO fibroblasts proliferated and migrated significantly slower than WT fibroblasts with or without TGF-β1.The proliferation and ECM production were enhanced by P2Y2 agonist PSB-1114 and inhibited by antagonist AR-C118925. TGF-β1 induced fibrotic activation was abolished by P2Y2 ablation and inhibited by AKT, ERK, and PKC inhibitors. Ablation of P2Y2 reduced denervation induced muscle atrophy and fibrosis.ConclusionsP2Y2 is a promoter of skeletal muscle atrophy and activation of fibroblasts after muscle injury, which signaling through AKT, ERK and PKC. P2Y2 could be a potential intervention target after muscle injury.
Highlights
Skeletal muscle atrophy and fibrosis are pathological conditions that contribute to morbidity in numerous conditions including aging, cachexia, and denervation
This study aims to investigate the role of P2Y2 receptor in the activation of myofibroblasts and skeletal muscle fibrosis
P2Y2 promotes the motility of skeletal muscle fibroblasts the role of P2Y2 in cell motility was assessed by Transwell migration assay
Summary
Skeletal muscle atrophy and fibrosis are pathological conditions that contribute to morbidity in numerous conditions including aging, cachexia, and denervation. Muscle atrophy may occurs as a systemic response to fasting and various diseases including cancer, AIDS, cardiac and renal failure, and sepsis or in specific muscles due to denervation or inactivity [1,2,3]. The degradation of both myofibrillar and soluble proteins is accelerated during atrophy. Fibroblasts produce the amority of the extracellular matrix (ECM) [11, 12] even though they only account for a small number of cells [13] These fibroblasts reside in the interstitial space between muscle fibers and play a critical role in maintaining muscle structure. Fibroblasts are required for muscle regeneration as the differentiation of satellite cells is premature and muscle fibers are poorly regenerated with decreased diameters when fibroblasts are ablated [14]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
