Page 132 - ebook

[B. Cell Biology/Stem Cell] B-1

Pathological Mechanism of a Constitutively Active Form of

Stromal Interaction Molecule 1 (STIM1) in Skeletal Muscle

Ji Hee Park¹,², Seung Yeon Jeong¹,², Jun Hee Choi¹,², Eun Hui Lee¹,²*

¹Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea,

²Department of Biomedicine & Health Sciences, Graduate School, The Catholic University of Korea, Seoul 06591,

Korea

STIM1 is the main protein that, along with Orai1, mediates SOCE in skeletal muscle. Abnormal SOCE due to
mutations in STIM1 is one of the causes of human skeletal muscle diseases. STIM1-R304Q 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. STIM1-R304Q did not interfere with

the terminal differentiation of skeletal myoblasts to myotubes and retained the ability of STIM1 to attenuate 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 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.