Abnormal Excitation-Contraction Coupling and Calcium Homeostasis in Myopathies and Cardiomyopathies

Abstract

Muscle contraction requires specialized membrane structures with precise geometry and relies on the concerted interplay of electrical stimulation and Ca 2+ release, known as excitation-contraction coupling (ECC). The membrane structure hosting ECC is called triad in skeletal muscle and dyad in cardiac muscle, and structural or functional defects of triads and dyads have been observed in a variety of myopathies and cardiomyopathies. Based on their function, the proteins localized at the triad/dyad can be classified into three molecular pathways: the Ca 2+ release complex (CRC), store-operated Ca 2+ entry (SOCE), and membrane remodeling. All three are mechanistically linked, and consequently, aberrations in any of these pathways cause similar disease entities. This review provides an overview of the clinical and genetic spectrum of triad and dyad defects with a main focus of attention on the underlying pathomechanisms.

Pathophysiological Effects of Overactive STIM1 on Murine Muscle Function and Structure

“…Functional investigations have shown that the mutations either alter the interaction with DHPR, or generate a leaky RyR1 Ca 2+ channel involving a constitutive cytosolic Ca 2+ overload [ 44 , 45 , 46 ]. In any case, the amount of released Ca 2+ upon membrane depolarization and DHPR activation is reduced, evidencing an uncoupling of excitation from contraction [ 47 ]. In analogy and reflecting significant ECC defects, the Stim1 R304W/+ mice manifested a delay in muscle force production and a downregulation of RyR1 and Cacna1s .…”

Mice with muscle-specific deletion of Bin1 recapitulate centronuclear myopathy and acute downregulation of dynamin 2 improves their phenotypes

“…CNM can be due to mutations in either MTM1, DNM2, BIN1 or SPEG genes, while mutations in additional genes as RYR1, TTN, CACNA1S, ZAK and PYROXD1 combine CNM features with other histological defects. [5][6][7] Of note, several of these gene products directly regulate excitationcontraction coupling at the skeletal muscle triad (RYR1, CACNA1S/Cav1.1) or membrane remodeling (BIN1, DNM2), leading to the hypothesis that defects in triad structure and function form a common disease cause. 8 BIN1 encodes amphiphysin 2, a protein sensing and controlling membrane curvature through its N-BAR (N-amphipathic Bin/Amphiphysin/Rvs) domain and recruiting through its SH3 (Src Homology) domain effectors like dynamins (DNM1 and DNM2) which tubulate and potentially fission membranes.…”

Sirtuin 3 overexpression preserves maximal sarco(endo)plasmic reticulum calcium ATPase activity in the skeletal muscle of mice subjected to high fat – high sucrose feeding

“…Excitation-contraction coupling (ECC) in skeletal muscle links electrical stimulation to calcium (Ca 2+ ) release from the sarcoplasmic reticulum (SR) and muscular contraction (Schartner et al 2019). Following contraction, intracellular Ca 2+ must be actively pumped by the sarco(endo)plasmic reticulum Ca 2+ ATPase (SERCA) from the cytosol back into the SR to allow for muscular relaxation (Stammers et al 2015).…”