Springer Science and Business Media LLC Acta Medica Okayama 2041-4889 16 1 2025 TRPV2 in muscle satellite cells is crucial for skeletal muscle remodelling 888 EN Yanzhu Chen Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kimiaki Katanosaka Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University Makoto Shibuya Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yubing Dong Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Lidan Zhang Laboratory of Stem Cell Regeneration and Adaptation, Graduate School of Pharmaceutical Sciences, The University of Osaka Motoi Kanagawa Department of Cell Biology and Molecular Medicine, Ehime University Graduate School of Medicine So-ichiro Fukada Laboratory of Stem Cell Regeneration and Adaptation, Graduate School of Pharmaceutical Sciences, The University of Osaka Keiji Naruse Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yuki Katanosaka Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Skeletal muscle remodelling relies on muscle stem cells (MuSCs) for regeneration after injury and hypertrophy in response to mechanical loading. However, the mechanisms that trigger MuSC activation and proliferation remain unclear. Transient receptor potential vanilloid 2 (TRPV2) ion channels respond to insulin-like growth factor-1 and mechanical stimuli to regulate the biological characteristics of various cells. Using a temporally inducible MuSC-specific conditional knockout (cKO) mouse, we show that TRPV2 regulates MuSC function and is essential for muscle remodelling. In cultured myofibre, MuSCs express TRPV2 and exhibit Ca2+ responses to the TRPV2 agonists 2-aminoethoxydiphenyl borate and probenecid, which are abolished upon TRPV2 deletion. TRPV2-deficient MuSCs exhibit reduced paired box 7 (Pax7) expression and impaired proliferation, suggesting TRPV2 is a factor that regulates the early stage of MuSC function. Myotube formation in MuSCs was enhanced by overexpression of TRPV2 and suppressed by TRPV2 deficiency, suggesting that TRPV2 is a factor that promotes myogenesis. Muscle-administered cardiotoxin promoted muscle regeneration and resulted in the appearance of numerous Pax7-positive MuSCs between myofibres. MuSC-specific TRPV2 cKO mice exhibit substantially impaired muscle regeneration after cardiotoxin-induced injury, drastically reducing Pax7-positive MuSCs between myofibres. In floxed mice, mechanical loading via synergist ablation induces hypertrophy and greatly increases the number of myonuclei per myofibre. In contrast, MuSC-specific TRPV2 cKO mice show no changes in myofibre thickness or nuclear number, either at baseline or after mechanical loading. Mechanical loading of floxed mice increased TRPV2+/Pax7+ double-positive MuSCs, but MuSC-specific TRPV2 cKO mice showed no change. Additionally, MuSCs exhibit Ca2+ responses to hypo-osmotic stimuli, which are suppressed by TRPV2 inhibitors and TRPV2 deletion, suggesting that MuSCs exhibit TRPV2-dependent mechanical responses. These results establish TRPV2 as a critical regulator of MuSC-mediated muscle remodelling, an important finding that may lead to therapeutic strategies for muscle repair and adaptation. No potential conflict of interest relevant to this article was reported.

Springer Science and Business Media LLC Acta Medica Okayama 1757-6512 16 1 2025 Specific induction of right ventricular-like cardiomyocytes from human pluripotent stem cells 519 EN Yukihiro Saito Department of Cardiovascular Medicine, Okayama University Hospital Kazufumi Nakamura Department of Cardiovascular Medicine, Okayama University Hospital Yuki Katanosaka Department of Cardiovascular Physiology, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences Toshihiro Iida Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Dai Kusumoto Department of Biomedical Informatics and Molecular Biology, The Sakaguchi Laboratory, Keio University School of Medicine Ryushi Sato Department of Bio-Informational Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka Riki Adachi Department of Bio-Informational Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka Satoshi Shimizu Department of Bio-Informational Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka Junko Kurokawa Department of Bio-Informational Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka Satoshi Akagi Department of Cardiovascular Medicine, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences Masashi Yoshida Department of Chronic Kidney Disease and Cardiovascular Disease, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences Toru Miyoshi Department of Cardiovascular Medicine, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences Hiroshi Morita Department of Cardiovascular Therapeutics, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences Keiji Naruse Department of Cardiovascular Physiology, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences Mikako Nishida Department of Metabolic Immune Regulation, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences Heiichiro Udono Department of Metabolic Immune Regulation, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences Jianhua Zhang Department of Medicine, University of Wisconsin School of Medicine and Public Health Shinsuke Yuasa Department of Cardiovascular Medicine, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences Timothy J. Kamp Department of Medicine, University of Wisconsin School of Medicine and Public Health Hiroshi Ito Department of Cardiovascular Medicine, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences Background Applications employing human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) require well-characterized, chamber-specific hPSC-CMs. Distinct first heart field (FHF) and second heart field (SHF) cardiac progenitor populations give rise to the left ventricular (LV) and right ventricular (RV) cardiomyocytes, respectively. This developmental difference in cardiomyocyte origin suggests that chamber-specific cardiomyocytes have unique characteristics. Therefore, efficient strategies to differentiate human pluripotent stem cells (hPSCs) specifically to LV-like or RV-like cardiomyocytes are needed and it is still unknown whether there is a phenotypic difference between LV-like cardiomyocytes and RV-like cardiomyocytes derived from hPSCs.<br> Methods An established hPSC cardiac differentiation protocol employing sequential GSK3ƒÀ inhibition followed by Wnt inhibition (GiWi) was modified by addition of insulin or BMP antagonists during mesoderm formation. Cardiac progenitor populations were evaluated for FHF and SHF markers, and differentiated hPSC-CMs were characterized for chamber-specific markers.<br> Results The GiWi protocol produced mainly FHF-like progenitor cells that gave rise to LV-like cardiomyocytes. Inhibition of endogenous BMP signaling during mesoderm induction using insulin or BMP antagonists reduced expression of FHF markers and increased expression of SHF markers in cardiac progenitor cells. hPSC-CMs arising from the SHF-like progenitor cells showed an RV-like gene expression pattern and exhibited phenotypic differences in spontaneous contraction rate, Ca2+ transients, and cell size compared to control LV-like cardiomyocytes.<br> Conclusion This study establishes methodology to generate RV-like hPSC-CMs to support the development of disease modeling research using chamber-specific hPSC-CMs. No potential conflict of interest relevant to this article was reported.

Nature Publishing Group Acta Medica Okayama 2041-1723 10 2019 Elimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure 5754 EN Yoshihiro Ujihara Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Motoi Kanagawa Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine Satoshi Mohri Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Satomi Takatsu Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Kazuhiro Kobayashi Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine Tatsushi Toda Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine Keiji Naruse Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yuki Katanosaka Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Heart failure is the major cause of death for muscular dystrophy patients, however, the molecular pathomechanism remains unknown. Here, we show the detailed molecular pathogenesis of muscular dystrophy-associated cardiomyopathy in mice lacking the fukutin gene (Fktn), the causative gene for Fukuyama muscular dystrophy. Although cardiac Fktn elimination markedly reduced alpha-dystroglycan glycosylation and dystrophin-glycoprotein complex proteins in sarcolemma at all developmental stages, cardiac dysfunction was observed only in later adulthood, suggesting that membrane fragility is not the sole etiology of cardiac dysfunction. During young adulthood, Fktn-deficient mice were vulnerable to pathological hypertrophic stress with downregulation of Akt and the MEF2-histone deacetylase axis. Acute Fktn elimination caused severe cardiac dysfunction and accelerated mortality with myocyte contractile dysfunction and disordered Golgi-microtubule networks, which were ameliorated with colchicine treatment. These data reveal fukutin is crucial for maintaining myocyte physiology to prevent heart failure, and thus, the results may lead to strategies for therapeutic intervention. No potential conflict of interest relevant to this article was reported.

Nature Publishing Group Acta Medica Okayama 2041-1723 5 2014 TRPV2 is critical for the maintenance of cardiac structure and function in mice 3932 EN Yuki Katanosaka Keiichiro Iwasaki Yoshihiro Ujihara Satomi Takatsu Koki Nishitsuji Motoi Kanagawa Atsushi Sudo Tatsushi Toda Kimiaki Katanosaka Satoshi Mohri Keiji Naruse The heart has a dynamic compensatory mechanism for haemodynamic stress. However, the molecular details of how mechanical forces are transduced in the heart are unclear. Here we show that the transient receptor potential, vanilloid family type 2 (TRPV2) cation channel is critical for the maintenance of cardiac structure and function. Within 4 days of eliminating TRPV2 from hearts of the adult mice, cardiac function declines severely, with disorganization of the intercalated discs that support mechanical coupling with neighbouring myocytes and myocardial conduction defects. After 9 days, cell shortening and Ca2+ handling by single myocytes are impaired in TRPV2-deficient hearts. TRPV2-deficient neonatal cardiomyocytes form no intercalated discs and show no extracellular Ca2+-dependent intracellular Ca2+ increase and insulin-like growth factor (IGF-1) secretion in response to stretch stimulation. We further demonstrate that IGF-1 receptor/PI3K/Akt pathway signalling is significantly downregulated in TRPV2-deficient hearts, and that IGF-1 administration partially prevents chamber dilation and impairment in cardiac pump function in these hearts. Our results improve our understanding of the molecular processes underlying the maintenance of cardiac structure and function. No potential conflict of interest relevant to this article was reported.

Okayama University Acta Medica Okayama 4 2014 Cardiac mechanosensitive integrator EN Yuki Katanosaka No potential conflict of interest relevant to this article was reported.