Disturbance in Z-disk mechanosensitive proteins induced by a persistent mutant myopalladin causes familial restrictive cardiomyopathy. Huby Anne-Cecile,Mendsaikhan Uzmee,Takagi Ken,Martherus Ruben,Wansapura Janaka,Gong Nan,Osinska Hanna,James Jeanne F,Kramer Kristen,Saito Kazuyoshi,Robbins Jeffrey,Khuchua Zaza,Towbin Jeffrey A,Purevjav Enkhsaikhan Journal of the American College of Cardiology BACKGROUND:Familial restrictive cardiomyopathy (FRCM) has a poor prognosis due to diastolic dysfunction and restrictive physiology (RP). Myocardial stiffness, with or without fibrosis, underlie RP, but the mechanism(s) of restrictive remodeling is unclear. Myopalladin (MYPN) is a messenger molecule that links structural and gene regulatory molecules via translocation from the Z-disk and I-bands to the nucleus in cardiomyocytes. Expression of N-terminal MYPN peptide results in severe disruption of the sarcomere. OBJECTIVES:The aim was to study a nonsense MYPN-Q529X mutation previously identified in the FRCM family in an animal model to explore the molecular and pathogenic mechanisms of FRCM. METHODS:Functional (echocardiography, cardiac magnetic resonance [CMR] imaging, electrocardiography), morphohistological, gene expression, and molecular studies were performed in knock-in heterozygote (Mypn(WT/Q526X)) and homozygote mice harboring the human MYPN-Q529X mutation. RESULTS:Echocardiographic and CMR imaging signs of diastolic dysfunction with preserved systolic function were identified in 12-week-old Mypn(WT/Q526X) mice. Histology revealed interstitial and perivascular fibrosis without overt hypertrophic remodeling. Truncated Mypn(Q526X) protein was found to translocate to the nucleus. Levels of total and nuclear cardiac ankyrin repeat protein (Carp/Ankrd1) and phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (Erk1/2), Erk1/2, Smad2, and Akt were reduced. Up-regulation was evident for muscle LIM protein (Mlp), desmin, and heart failure (natriuretic peptide A [Nppa], Nppb, and myosin heavy chain 6) and fibrosis (transforming growth factor beta 1, alpha-smooth muscle actin, osteopontin, and periostin) markers. CONCLUSIONS:Heterozygote Mypn(WT/Q526X) knock-in mice develop RCM due to persistence of mutant Mypn(Q526X) protein in the nucleus. Down-regulation of Carp and up-regulation of Mlp and desmin appear to augment fibrotic restrictive remodeling, and reduced Erk1/2 levels blunt a hypertrophic response in Mypn(WT/Q526X) hearts. 10.1016/j.jacc.2014.09.071

Vitamin C Promotes Muscle Development Mediated by the Interaction of CSRP3 with MyoD and MyoG. Journal of agricultural and food chemistry Previous studies have reported that vitamin C (VC), an essential nutrient, exerts beneficial effects on muscle health. However, the molecular mechanism involved in the VC-mediated regulation of muscle development is still unclear. The roles of VC in muscle development and the underlying molecular mechanisms were examined using cell and molecular biology, transcriptomics, proteomics, and animal experiments in this study. VC upregulated the expression of sodium-dependent vitamin C transporter 2 (SVCT2) and cysteine rich protein 3 (CSRP3). Additionally, VC promoted the differentiation of C2C12 cells and the repair of mouse muscle injury by upregulating the nuclear translocation of CSRP3, which subsequently interacted with MyoD and MyoG. This study provided a theoretical basis for elucidating the mechanism underlying the VC-mediated regulation of muscle development, as well as for developing animal nutritional supplements and therapeutic drugs for muscle diseases. 10.1021/acs.jafc.2c02432

Dynein-mediated nuclear translocation of yes-associated protein through microtubule acetylation controls fibroblast activation. Cellular and molecular life sciences : CMLS Myofibroblasts are the major cell type that is responsible for increase in the mechanical stiffness in fibrotic tissues. It has well documented that the TGF-β/Smad axis is required for myofibroblast differentiation under the rigid substrate condition. However, the mechanism driving myofibroblast differentiation in soft substrates remains unknown. In this research, we demonstrated that interaction of yes-associated protein (YAP) and acetylated microtubule via dynein, a microtubule motor protein drives nuclear localization of YAP in the soft matrix, which in turn increased TGF-β1-induced transcriptional activity of Smad for myofibroblast differentiation. Pharmacological and genetical disruption of dynein impaired the nuclear translocation of YAP and decreased the TGF-β1-induced Smad activity even though phosphorylation and nuclear localization of Smad occurred normally in α-tubulin acetyltransferase 1 (α-TAT1) knockout cell. Moreover, microtubule acetylation prominently appeared in the fibroblast-like cells nearby the blood vessel in the fibrotic liver induced by CCl administration, which was conversely decreased by TGF-β receptor inhibitor. As a result, quantitative inhibition of microtubule acetylation may be suggested as a new target for overcoming fibrotic diseases. 10.1007/s00018-019-03412-x