Ca sparks are the elementary units of Ca-induced Ca release (CICR) in striated muscle cells revealed as localized Ca release events from sarcoplasmic reticulum (SR) by confocal microscopy. While Ca sparks are well defined in cardiac muscle, there has been a general belief that these localized Ca release events are rare in intact adult mammalian skeletal muscle. As a result of the intrinsic difficulties in monitoring Ca spark activity in intact mammalian muscle, the cellular and molecular mechanisms underlying the regulation of CICR in muscle function and the adaptive changes of CICR in muscle aging and dystrophy remain largely unexplored. Recently, we discovered that stress generated by membrane deformation induces a robust Ca spark response spatially confined in close proximity to the sarcolemmal membrane in healthy young mammalian muscles. These induced Ca sparks are repeatable and reversible in young muscle fibers, but become transient and static in aged skeletal muscle. In dystrophic muscle with fragile membrane integrity, induced Ca sparks are irreversible and penetrate from the periphery to the fiber interior. Thus, uncontrolled Ca spark activity could potentially lead to partial depletion of the SR Ca store, triggering increased store- operated Ca entry (SOCE) and providing a dystrophic signal in mammalian skeletal muscle. We hypothesize that Ca sparks can be used as a measure of the plastic nature of CICR in muscle health, aging and dystrophy. Experiments proposed in this project shall focus on addressing the following fundamental questions regarding the physiological function of Ca sparks in skeletal muscle: First, what are the cellular factors that are responsible for the peripheral distribution and the plasticity of Ca sparks in young, healthy skeletal muscle? Second, is there dynamic bi-directional coupling between Ca sparks and SOCE, and does alteration of this coupling produce muscle dysfunction? Third, how do triad-junction resident proteins influence Ca spark function in health, aging and disease? As defects in control of CICR have been linked to numerous pathologic states, including heart failure and neurodegenerative conditions, we hope knowledge gained from our studies will not only help establish the physiological function of stress-induced Ca sparks in skeletal muscle fibers, they may also point to potential therapeutic targets in excitable cells where dysfunction of CICR has been observed.

Public Health Relevance

Decline in skeletal muscle function is a major contributor to decreased mobility and independence in the elderly, which leads to deterioration of quality of life. Identification of molecular makers of muscle aging and their contribution to aging-related muscle dysfunction has recently emerged as a major focus in biomedical research. This project originates from our discovery of MG29 as a key regulator of muscle function associated with aging. The studies proposed here focus on establishing the proof-of-principle data for targeting MG29 function in treatment of muscle aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG028614-08
Application #
8442832
Study Section
Special Emphasis Panel (ZRG1-MOSS-T (02))
Program Officer
Williams, John
Project Start
2006-09-01
Project End
2017-03-31
Budget Start
2013-05-15
Budget End
2014-03-31
Support Year
8
Fiscal Year
2013
Total Cost
$372,058
Indirect Cost
$129,280
Name
Ohio State University
Department
Surgery
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Correll, Robert N; Lynch, Jeffrey M; Schips, Tobias G et al. (2017) Mitsugumin 29 regulates t-tubule architecture in the failing heart. Sci Rep 7:5328
Karam, Chehade; Yi, Jianxun; Xiao, Yajuan et al. (2017) Absence of physiological Ca2+transients is an initial trigger for mitochondrial dysfunction in skeletal muscle following denervation. Skelet Muscle 7:6
Xu, Li; Park, Ki Ho; Zhao, Lixia et al. (2016) CRISPR-mediated Genome Editing Restores Dystrophin Expression and Function in mdx Mice. Mol Ther 24:564-9
Ahn, Mi Kyoung; Lee, Keon Jin; Cai, Chuanxi et al. (2016) Mitsugumin 53 regulates extracellular Ca2+ entry and intracellular Ca2+ release via Orai1 and RyR1 in skeletal muscle. Sci Rep 6:36909
Yao, Yonggang; Zhang, Bo; Zhu, Hua et al. (2016) MG53 permeates through blood-brain barrier to protect ischemic brain injury. Oncotarget 7:22474-85
Lin, Pei-Hui; Duann, Pu; Komazaki, Shinji et al. (2015) Lysosomal two-pore channel subtype 2 (TPC2) regulates skeletal muscle autophagic signaling. J Biol Chem 290:3377-89
Pan, Zui; Ma, JianJie (2015) Open Sesame: treasure in store-operated calcium entry pathway for cancer therapy. Sci China Life Sci 58:48-53
Woo, Jin Seok; Hwang, Ji-Hye; Huang, Mei et al. (2015) Interaction between mitsugumin 29 and TRPC3 participates in regulating Ca(2+) transients in skeletal muscle. Biochem Biophys Res Commun 464:133-9
Liu, Jianxun; Zhu, Hua; Zheng, Yongqiu et al. (2015) Cardioprotection of recombinant human MG53 protein in a porcine model of ischemia and reperfusion injury. J Mol Cell Cardiol 80:10-19
Huang, Jiaqing; Sun, Mingzhai; Gumpper, Kristyn et al. (2015) 3D multifocus astigmatism and compressed sensing (3D MACS) based superresolution reconstruction. Biomed Opt Express 6:902-17

Showing the most recent 10 out of 36 publications