Mitsugumin 29 (MG29) is a muscle-specific member of the synaptophysin family proteins that participates in controlling the maturation and development of the transverse-tubule (TT) structure and the maintenance of intracellular Ca2+ signaling in skeletal muscle. Genetic ablation of mg29 leads to defective TT structure in skeletal muscle, which show similarity to the abnormal TT network observed in animal models of, and human patients with, muscular dystrophy. The principal investigator of this application has obtained evidence that revealed an essential role for MG29 in controlling the TT membrane network in muscle physiology and diseases. Immunoblot showed that expression of MG29 was reduced in both human and mice with muscular dystrophy, indicating the possibility that MG29 may be involved in the development of muscular dystrophy. Using biochemical assay, we identified a functional interaction between MG29, dysferlin and Bin1, other TT- resident proteins with important roles in muscular dystrophy. Toward understanding the biological function for MG29 in control of TT biogenesis, we used the HMCL-7304 myoblast cell line derived from human muscle. Cultured myotubes derived from HMCL-7304 cells do not express MG29 and lack TT network. Preliminary study with rescue of MG29 in HMCL-7304 myotubes revealed the initiation of TT membranes. Establishing an in vitro system with control of TT membrane can potentially be a useful tool for muscle physiology research. The mg29 gene contains a unique 3' untranslated region (UTR) with potential binding sites for microRNA (miRNA) or RNA-stabilizing factors. Mutagenesis studies revealed that miR-181a could target a region in the 3'UTR that is highly conserved between mouse and human mg29 genes to exhibit a strong control of MG29 expression in skeletal muscle. Studies from other investigators have shown that miR-181 was significantly elevated in human patients with muscular dystrophy. These data suggest an intriguing possibility that elevated miR-181a may be a contributing factor for the reduced MG29 expression under muscular dystrophic conditions. Experiments outlined in this proposal will focus on testing the hypothesis that MG29 is an integral component of TT biogenesis in skeletal muscle, and miRNA-mediated control of MG29 expression contributes to changes in TT integrity during muscular dystrophy. First, by using in vitro cell culture and in vivo transgenic animal approaches, we will discern the biological function for MG29 in control of TT integrity and remodeling in muscle physiology and dystrophy. Second, we will elucidate the mechanisms that underlie miRNA-mediated control of MG29 expression in skeletal muscle, and to identify the mechanisms that contribute to reduction of MG29 in dystrophic muscle. Using AAV-mediated gene delivery of antagomir into the mdx mice, we will test whether suppression of miRNA-mediated down-regulation of MG29 expression can improve TT structure and rescue muscle strength in dystrophic muscle.
A major challenge in the field of excitation-contraction coupling is understanding the molecular machinery that contribute to the assembly of transverse tubular (TT) network in skeletal muscle. In this project, we study the biological function of a gen named mg29 and its interacting partners in control of biogenesis of TT structure in skeletal muscle physiology and diseases.
|Peng, Bao-Yu; Wang, Qiang; Luo, Yan-Hong et al. (2018) A novel and quick PCR-based method to genotype mice with a leptin receptor mutation (db/db mice). Acta Pharmacol Sin 39:117-123|
|Luo, Yanhong; He, Jianfeng; Yang, Chunlin et al. (2018) UCH-L1 promotes invasion of breast cancer cells through activating Akt signaling pathway. J Cell Biochem 119:691-700|
|Zhang, Jiu-Cheng; Chen, Wei-Dong; Alvarez, Jean Bustamante et al. (2018) Cancer immune checkpoint blockade therapy and its associated autoimmune cardiotoxicity. Acta Pharmacol Sin 39:1693-1698|
|An, Xin; Sarmiento, Cesar; Tan, Tao et al. (2017) Regulation of multidrug resistance by microRNAs in anti-cancer therapy. Acta Pharm Sin B 7:38-51|
|Li, Mi; Li, Haichang; Li, Xiangguang et al. (2017) A Bioinspired Alginate-Gum Arabic Hydrogel with Micro-/Nanoscale Structures for Controlled Drug Release in Chronic Wound Healing. ACS Appl Mater Interfaces 9:22160-22175|
|Sermersheim, Matthew A; Park, Ki Ho; Gumpper, Kristyn et al. (2017) MicroRNA regulation of autophagy in cardiovascular disease. Front Biosci (Landmark Ed) 22:48-65|
|Chen, Ken; Xu, Zaicheng; Liu, Yukai et al. (2017) Irisin protects mitochondria function during pulmonary ischemia/reperfusion injury. Sci Transl Med 9:|