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Interaction between mitsugumin 29 and TRPC3 participates in regulating Ca(2+) transients in skeletal muscle.

ABSTRACT: Mitsugumin 29 (MG29) is related to the fatigue and aging processes of skeletal muscle. To examine the roles of MG29 in conjunction with its binding protein, the canonical-type transient receptor potential cation channel 3 (TRPC3), in skeletal muscle, the binding region of MG29 to TRPC3 was studied along with the functional relevance of the binding in mouse primary skeletal myotubes using co-immunoprecipitation assays and Ca(2+) imaging experiments. The N-terminus and the I-II loop of MG29 constitute the binding region for TRPC3. The myotubes that expressed the MG29 mutant missing the entire TRPC3-binding region showed a disrupted binding between endogenous MG29 and TRPC3 and a reduction in Ca(2+) transients in response to membrane depolarization without affecting ryanodine receptor 1 activity, the resting cytosolic Ca(2+) level, and the amount of releasable Ca(2+) from the sarcoplasmic reticulum. Among the proteins mediating Ca(2+) movements in skeletal muscle, TRPC4 expression was significantly decreased by the MG29 mutant. Therefore, MG29 could be a new factor for regulating Ca(2+) transients during skeletal muscle contraction possibly via a correlation with TRPC3 and TRPC4.

SUBMITTER: Woo JS

PROVIDER: S-EPMC4535989 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Interaction between mitsugumin 29 and TRPC3 participates in regulating Ca(2+) transients in skeletal muscle.

Woo Jin Seok JS Hwang Ji-Hye JH Huang Mei M Ahn Mi Kyoung MK Cho Chung-Hyun CH Ma Jianjie J Lee Eun Hui EH

Biochemical and biophysical research communications 20150630 1

Mitsugumin 29 (MG29) is related to the fatigue and aging processes of skeletal muscle. To examine the roles of MG29 in conjunction with its binding protein, the canonical-type transient receptor potential cation channel 3 (TRPC3), in skeletal muscle, the binding region of MG29 to TRPC3 was studied along with the functional relevance of the binding in mouse primary skeletal myotubes using co-immunoprecipitation assays and Ca(2+) imaging experiments. The N-terminus and the I-II loop of MG29 consti ...[more]

PMID: 26141232

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Project description:There is substantial evidence indicating that disruption of Ca(2+) homeostasis and activation of cytosolic proteases play a key role in the pathogenesis and progression of Duchenne Muscular Dystrophy (DMD). However, the exact nature of the Ca(2+) deregulation and the Ca(2+) signaling pathways that are altered in dystrophic muscles have not yet been resolved. Here we examined the contribution of the store-operated Ca(2+) entry (SOCE) for the pathogenesis of DMD. RT-PCR and Western blot found that the expression level of Orai1, the pore-forming unit of SOCE, was significantly elevated in the dystrophic muscles, while parallel increases in SOCE activity and SR Ca(2+) storage were detected in adult mdx muscles using Fura-2 fluorescence measurements. High-efficient shRNA probes against Orai1 were delivered into the flexor digitorum brevis muscle in live mice and knockdown of Orai1 eliminated the differences in SOCE activity and SR Ca(2+) storage between the mdx and wild type muscle fibers. SOCE activity was repressed by intraperitoneal injection of BTP-2, an Orai1 inhibitor, and cytosolic calpain1 activity in single muscle fibers was measured by a membrane-permeable calpain substrate. We found that BTP-2 injection for 2 weeks significantly reduced the cytosolic calpain1 activity in mdx muscle fibers. Additionally, ultrastructural changes were observed by EM as an increase in the number of triad junctions was identified in dystrophic muscles. Compensatory changes in protein levels of SERCA1, TRP and NCX3 appeared in the mdx muscles, suggesting that comprehensive adaptations occur following altered Ca(2+) homeostasis in mdx muscles. Our data indicates that upregulation of the Orai1-mediated SOCE pathway and an overloaded SR Ca(2+) store contributes to the disrupted Ca(2+) homeostasis in mdx muscles and is linked to elevated proteolytic activity, suggesting that targeting Orai1 activity may be a promising therapeutic approach for the prevention and treatment of muscular dystrophy.

Dataset Information

Interaction between mitsugumin 29 and TRPC3 participates in regulating Ca(2+) transients in skeletal muscle.

Publications

Interaction between mitsugumin 29 and TRPC3 participates in regulating Ca(2+) transients in skeletal muscle.

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