Skeletal myogenesis is precisely regulated by multiple transcription factors. Previously, we demonstrated that enhancer of polycomb 1 (Epc1) induces skeletal muscle differentiation by potentiating serum response factor (SRF)-dependent muscle gene activation. Here, we report that an interacting partner of Epc1, ret finger protein (RFP), blocks skeletal muscle differentiation. Our findings show that RFP was highly expressed in skeletal muscles and was downregulated during myoblast differentiation. Forced expression of RFP delayed myoblast differentiation, whereas knockdown enhanced it. Epc1-induced enhancements of SRF-dependent multinucleation, transactivation of the skeletal a-actin promoter, binding of SRF to the serum response element, and muscle-specific gene induction were blocked by RFP. RFP interfered with the physical interaction between Epc1 and SRF. Muscles from rfp knockout mice (Rfp À/À ) mice were bigger than those from wild-type mice, and the expression of SRF-dependent muscle-specific genes was upregulated. Myotube formation and myoblast differentiation were enhanced in Rfp À/À mice. Taken together, our findings highlight RFP as a novel regulator of muscle differentiation that acts by modulating the expression of SRFdependent skeletal muscle-specific genes. Skeletal muscle is critical for the generation of active force, the maintenance of posture, and body shape. Muscle regeneration from myoblasts is important for the repair and maintenance of skeletal muscles after muscle injury or dystrophy. Myogenesis from the precursor cells to the skeletal muscle lineage consists of multiple steps, and each of these steps is tightly organized by extrinsic and intrinsic signaling pathways. Thus, not only for understanding the regeneration of injured skeletal muscles, but also for furthering therapeutic approaches to muscle atrophy, a hot issue in current research is how the proliferation and differentiation of myoblasts are regulated. To ultimately provide important clues for therapeutics, a comprehensive understanding of how various signaling mechanisms collaborate to regulate the gene expression and epigenetic programs for myoblast differentiation is needed.The TRIM (tripartite motif) protein family (also known as the RBCC protein family) has the common structures of three zinc-binding domains, a RING, a B-box type 1, and a B-box type 2, followed by a coiled-coil region.
BackgroundAlthough OA is regarded as a disease of the articular cartilage, recent research has demonstrated whole-joint pathology, including synovial inflammation, subchondral bone sclerosis, osteophyte formation, and changes in periarticular muscles that surround the affected joint. There is also increasing evidence that the consequences of knee OA are associated with decreased lower limb muscle strength and function. It is unclear whether the change in periarticular muscle is the cause or result of disease progression, however.ObjectivesThis study investigated changes in periarticular muscle during the progression of osteoarthritis (OA), as well as the cause-and-effect relationship between muscle weakness and OA, in a mouse model of OA achieved by destabilization of the medial meniscus (DMM).MethodsKnee OA was induced by DMM in 10-week-old male C57BL/6 mice. Pathological muscle phenotypes in the tibialis anterior (TA) and quadriceps muscles were assessed in both the early and late stages of OA with muscle-fiber cross-sectional area analysis, markers of myogenesis, as well as the proliferation of satellite cells. OA pathology and pain behavior were examined with OARSI grade, von Frey filament threshold and pressure algometer. Periarticular muscle weakness was induced by multiple rounds of barium chloride injections after DMM induction. In addition, myostatin knockout.mice with muscle hypertrophy phenotype was used to evaluate the influence of muscle mass on pain and joint destruction after DMM.ResultsMorphological alterations in the TA and quadriceps in DMM mice included variations in muscle-fiber size, aberrant muscle fibrosis, inflammatory cell infiltration, and decreased muscle mass. Periarticular muscle fibers isolated from DMM mice showed reductions in cell number and myogenic capacity, as well as the proliferation of satellite cells. DMM mice exhibited exacerbated articular cartilage destruction, subchondral bone sclerosis, synovitis and pain after muscle injury compared to the DMM + vehicle group. Myostatin knockout mice were characterized by attenuated OA and the complete abrogation of pain behavior after DMM.ConclusionDMM-induced knee OA resulted in morphological changes in periarticular muscle, in a manner that coincided with muscle atrophy. Joint destruction and pain after DMM were aggravated by muscle weakness and alleviated by muscle hypertrophy. Our results suggest a causative role for muscle weakness in the progression of joint damage and pain in OA.References[1]Silva JMS, Alabarse PVG, Teixeira VON, et al. Muscle wasting in osteoarthritis model induced by anterior cruciate ligament transection. PLoS One 2018;13(4):e0196682.[2]Cunha JE, Barbosa GM, Castro P, et al. Knee osteoarthritis induces atrophy and neuromuscular junction remodeling in the quadriceps and tibialis anterior muscles of rats. Sci Rep 2019;9(1):6366.[3]Rehan Youssef A, Longino D, Seerattan R, et al. Muscle weakness causes joint degeneration in rabbits. Osteoarthritis Cartilage 2009;17(9):1228-35.[4]Noehren B, Kosmac K, Walton RG, et al. Alterations in quadriceps muscle cellular and molecular properties in adults with moderate knee osteoarthritis. Osteoarthritis Cartilage 2018;26(10):1359-68.[5]Baek KW, Jung YK, Kim JS, et al. Rodent Model of Muscular Atrophy for Sarcopenia Study. J Bone Metab 2020;27(2):97-110.[6]St Andre M, Johnson M, Bansal PN, et al. A mouse anti-myostatin antibody increases muscle mass and improves muscle strength and contractility in the mdx mouse model of Duchenne muscular dystrophy and its humanized equivalent, domagrozumab (PF-06252616), increases muscle volume in cynomolgus monkeys. Skelet Muscle 2017;7(1):2Acknowledgements:NIL.Disclosure of InterestsHyun Ah Kim Consultant of: ICM Co., Ltd. Building 102, Room 455, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, ROK 2019- present Concultation on clinical aspect of RA and OA paid amount 5,000 per year, Hyun Sook Hwang: None declared, Ju-Ryoung Kim: None declared.
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