Pathological Mechanism of a Constitutively Active Form of Stromal Interaction Molecule 1 in Skeletal Muscle.

Ji Hee Park,Jun Hee Choi,Seung Yeon Jeong,Eun Hui Lee

doi:10.3390/biom11081064

Ji Hee Park, Jun Hee Choi + Show 2 more

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https://doi.org/10.3390/biom11081064

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Journal: Biomolecules	Publication Date: Jul 21, 2021
Citations: 2	License type: CC BY 4.0

Affiliation: Catholic University of Korea

Abstract

Stromal interaction molecule 1 (STIM1) is the main protein that, along with Orai1, mediates store-operated Ca2+ entry (SOCE) in skeletal muscle. Abnormal SOCE due to mutations in STIM1 is one of the causes of human skeletal muscle diseases. STIM1-R304Q (a constitutively active form of STIM1) has been found in human patients with skeletal muscle phenotypes such as muscle weakness, myalgia, muscle stiffness, and contracture. However, the pathological mechanism(s) of STIM1-R304Q in skeletal muscle have not been well studied. To examine the pathological mechanism(s) of STIM1-R304Q in skeletal muscle, STIM1-R304Q was expressed in mouse primary skeletal myotubes, and the properties of the skeletal myotubes were examined using single-myotube Ca2+ imaging, transmission electron microscopy (TEM), and biochemical approaches. STIM1-R304Q did not interfere with the terminal differentiation of skeletal myoblasts to myotubes and retained the ability of STIM1 to attenuate dihydropyridine receptor (DHPR) activity. STIM1-R304Q induced hyper-SOCE (that exceeded the SOCE by wild-type STIM1) by affecting both the amplitude and the onset rate of SOCE. Unlike that by wild-type STIM1, hyper-SOCE by STIM1-R304Q contributed to a disturbance in Ca2+ distribution between the cytosol and the sarcoplasmic reticulum (SR) (high Ca2+ in the cytosol and low Ca2+ in the SR). Moreover, the hyper-SOCE and the high cytosolic Ca2+ level induced by STIM1-R304Q involve changes in mitochondrial shape. Therefore, a series of these cellular defects induced by STIM1-R304Q could induce deleterious skeletal muscle phenotypes in human patients carrying STIM1-R304Q.

Highlights

Initiation of skeletal muscle contraction is mediated by excitation–contraction (EC)coupling [1,2,3]
To study the pathological mechanism of Stromal interaction molecule 1 (STIM1)-R304Q in skeletal muscle (Figure 1A), wild-type STIM1 or STIM1-R304Q was expressed in mouse primary skeletal myotubes (Figure 1B)
No significant difference was induced in myotube width by the expression of wild-type STIM1 (wtSTIM1) or STIM1-R304Q

Summary

Introduction

Initiation of skeletal muscle contraction is mediated by excitation–contraction (EC)coupling [1,2,3]. (RyR1) on the sarcoplasmic reticulum (SR) membrane (by physical interactions between active DHPR and RyR1), and (3) Ca2+ release from the SR to the cytosol through active. The change in intracellular Ca2+ levels is a messenger event that connects membrane depolarization to muscle contraction during skeletal muscle contraction. In addition to the initiation of skeletal muscle contraction, the maintenance of high cytosolic Ca2+ levels during skeletal muscle contractions, such as long periods or repetitive contractions, is another important issue to understand skeletal muscle contraction. Extracellular Ca2+ entry contributes to the maintenance of high cytosolic Ca2+ levels during skeletal muscle contractions, and store-operated Ca2+ entry (SOCE) is the main extracellular Ca2+ entry method in skeletal muscle [2,3].

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