Alteration of STIM1/Orai1-Mediated SOCE in Skeletal Muscle: Impact in Genetic Muscle Diseases and Beyond

Abstract

Intracellular Ca2+ ions represent a signaling mediator that plays a critical role in regulating different muscular cellular processes. Ca2+ homeostasis preservation is essential for maintaining skeletal muscle structure and function. Store-operated Ca2+ entry (SOCE), a Ca2+-entry process activated by depletion of intracellular stores contributing to the regulation of various function in many cell types, is pivotal to ensure a proper Ca2+ homeostasis in muscle fibers. It is coordinated by STIM1, the main Ca2+ sensor located in the sarcoplasmic reticulum, and ORAI1 protein, a Ca2+-permeable channel located on transverse tubules. It is commonly accepted that Ca2+ entry via SOCE has the crucial role in short- and long-term muscle function, regulating and adapting many cellular processes including muscle contractility, postnatal development, myofiber phenotype and plasticity. Lack or mutations of STIM1 and/or Orai1 and the consequent SOCE alteration have been associated with serious consequences for muscle function. Importantly, evidence suggests that SOCE alteration can trigger a change of intracellular Ca2+ signaling in skeletal muscle, participating in the pathogenesis of different progressive muscle diseases such as tubular aggregate myopathy, muscular dystrophy, cachexia, and sarcopenia. This review provides a brief overview of the molecular mechanisms underlying STIM1/Orai1-dependent SOCE in skeletal muscle, focusing on how SOCE alteration could contribute to skeletal muscle wasting disorders and on how SOCE components could represent pharmacological targets with high therapeutic potential.

Ryanodine receptor 1 (RYR1) mutations in two patients with tubular aggregate myopathy

“…On the other hand, it is known that RYR1 mutations, although present in different regions of the RYR1 sequence (Amburgey et al, 2013; Galli et al, 2006; Robinson et al, 2006) do not show any correlation between mutation location, RyR1 channel activity and clinical phenotype (Amburgey et al, 2013; Todd et al, 2018). An additional intriguing aspect emerging from the data we are reporting is that the allele frequency in the general population of the two causative RYR1 mutations (1:47,102 and 1:25,696 for p.Thr2206Met and p.Gly2434Arg, respectively) is much higher than the frequency of a very rare disease such as TAM (Conte et al, 2021; Silva‐Rojas et al, 2020). This apparent contradiction could be, at least in part, explained by considering that causative RYR1 mutations may have reduced penetrance (Ibarra Moreno et al, 2019; Shaw & Hopkins, 2019).…”

Analysis of dog breed diversity using a composite selection index

“…The regions identified in the analysis of Xi dogs included genes that are central to these processes, most notably those involved in cerebellar function, excitation–contraction coupling in muscle and muscle development. The top ranked region on CFA25 contained the Transient Receptor Potential Cation Channel Subfamily C Member 4 (TRPC4) gene, which codes for a protein that, together with TRPC1 and stromal-interacting molecule-1 (STIM1) , is an important regulator of a process known as store-operated calcium entry (SOCE) 43 , 44 . This process is critical for optimal skeletal muscle function during exercise when there are repetitive sarcolemma membrane depolarizations.…”

Analysis of dog breed diversity using a composite selection index.

“…The regions identified in the analysis of Xi dogs included genes that are central to these processes, most notably those involved in cerebellar function, excitation-contraction coupling in muscle and muscle development. The top ranked region on CFA25 contained the Transient Receptor Potential Cation Channel Subfamily C Member 4 (TRPC4) gene, which codes for a protein that, together with TRPC1 and stromal-interacting molecule-1 (STIM1), is an important regulator of a process known as store-operated calcium entry (SOCE) 33,34 . This process is critical for optimal skeletal muscle function during exercise when there are repetitive sarcolemma membrane depolarizations.…”