Pathological Mechanism of a Constitutively Active Form of Stromal Interaction Molecule 1 in Skeletal Muscle
Stromal interaction molecule 1 (STIM1) is the main protein that, along with Orai1, mediates store-operated Ca<sup>2+</sup> 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...
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MDPI AG
2021-07-01
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| Online Access: | https://www.mdpi.com/2218-273X/11/8/1064 |
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| author | Ji Hee Park Seung Yeon Jeong Jun Hee Choi Eun Hui Lee |
| author_facet | Ji Hee Park Seung Yeon Jeong Jun Hee Choi Eun Hui Lee |
| author_sort | Ji Hee Park |
| collection | DOAJ |
| description | Stromal interaction molecule 1 (STIM1) is the main protein that, along with Orai1, mediates store-operated Ca<sup>2+</sup> 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 Ca<sup>2+</sup> 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 Ca<sup>2+</sup> distribution between the cytosol and the sarcoplasmic reticulum (SR) (high Ca<sup>2+</sup> in the cytosol and low Ca<sup>2+</sup> in the SR). Moreover, the hyper-SOCE and the high cytosolic Ca<sup>2+</sup> 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. |
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| language | English |
| last_indexed | 2024-03-10T08:59:55Z |
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| series | Biomolecules |
| spelling | doaj.art-eed3c783948c49e79c6f8db87b2d94f82023-11-22T06:54:16ZengMDPI AGBiomolecules2218-273X2021-07-01118106410.3390/biom11081064Pathological Mechanism of a Constitutively Active Form of Stromal Interaction Molecule 1 in Skeletal MuscleJi Hee Park0Seung Yeon Jeong1Jun Hee Choi2Eun Hui Lee3Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul 06591, KoreaDepartment of Physiology, College of Medicine, The Catholic University of Korea, Seoul 06591, KoreaDepartment of Physiology, College of Medicine, The Catholic University of Korea, Seoul 06591, KoreaDepartment of Physiology, College of Medicine, The Catholic University of Korea, Seoul 06591, KoreaStromal interaction molecule 1 (STIM1) is the main protein that, along with Orai1, mediates store-operated Ca<sup>2+</sup> 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 Ca<sup>2+</sup> 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 Ca<sup>2+</sup> distribution between the cytosol and the sarcoplasmic reticulum (SR) (high Ca<sup>2+</sup> in the cytosol and low Ca<sup>2+</sup> in the SR). Moreover, the hyper-SOCE and the high cytosolic Ca<sup>2+</sup> 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.https://www.mdpi.com/2218-273X/11/8/1064skeletal muscleSTIM1hyper-SOCEcytosolic Ca<sup>2+</sup> |
| spellingShingle | Ji Hee Park Seung Yeon Jeong Jun Hee Choi Eun Hui Lee Pathological Mechanism of a Constitutively Active Form of Stromal Interaction Molecule 1 in Skeletal Muscle Biomolecules skeletal muscle STIM1 hyper-SOCE cytosolic Ca<sup>2+</sup> |
| title | Pathological Mechanism of a Constitutively Active Form of Stromal Interaction Molecule 1 in Skeletal Muscle |
| title_full | Pathological Mechanism of a Constitutively Active Form of Stromal Interaction Molecule 1 in Skeletal Muscle |
| title_fullStr | Pathological Mechanism of a Constitutively Active Form of Stromal Interaction Molecule 1 in Skeletal Muscle |
| title_full_unstemmed | Pathological Mechanism of a Constitutively Active Form of Stromal Interaction Molecule 1 in Skeletal Muscle |
| title_short | Pathological Mechanism of a Constitutively Active Form of Stromal Interaction Molecule 1 in Skeletal Muscle |
| title_sort | pathological mechanism of a constitutively active form of stromal interaction molecule 1 in skeletal muscle |
| topic | skeletal muscle STIM1 hyper-SOCE cytosolic Ca<sup>2+</sup> |
| url | https://www.mdpi.com/2218-273X/11/8/1064 |
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