SPEG-deficient skeletal muscles exhibit abnormal triad and defective calcium handling

Abstract

Centronuclear myopathies (CNM) are a subtype of congenital myopathies (CM) characterized by skeletal muscle weakness and an increase in the number of central myonuclei. We have previously identified three CNM probands, two with associated dilated cardiomyopathy, carrying striated preferentially expressed gene (SPEG) mutations. Currently, the role of SPEG in skeletal muscle function is unclear as constitutive SPEG-deficient mice developed severe dilated cardiomyopathy and died in utero. We have generated a conditional Speg-KO mouse model and excised Speg by crosses with striated muscle-specific cre-expressing mice (MCK-Cre). The resulting litters had a delay in Speg excision consistent with cre expression starting in early postnatal life and, therefore, an extended lifespan up to a few months. KO mice were significantly smaller and weaker than their littermate-matched controls. Histopathological skeletal muscle analysis revealed smaller myofibers, marked fiber-size variability, and poor integrity and low number of triads. Further, SPEG-deficient muscle fibers were weaker by physiological and in vitro studies and exhibited abnormal Ca2+ handling and excitation-contraction (E-C) coupling. Overall, SPEG deficiency in skeletal muscle is associated with fewer and abnormal triads, and defective calcium handling and excitation-contraction coupling, suggesting that therapies targeting calcium signaling may be beneficial in such patients.

Pressure Overload in Mice With Haploinsufficiency of Striated Preferentially Expressed Gene Leads to Decompensated Heart Failure

“…Only recently, it has been reported that acute loss of Speg leads to heart failure in adult mice and is associated with a disruption in transverse tubule integrity, calcium handling, and junctional membrane complex activity ( Quick et al, 2017 ). These findings are consistent with the fact that Speg deficiency in the skeletal muscle compartment results in abnormal triad development (formed by transverse tubules and sarcoplasmic reticulum), and faulty calcium handling and excitation-contraction coupling ( Huntoon et al, 2018 ). In the present study we assessed cardiac function in the small cohort of Speg −/− mice that survived to adulthood ( Liu et al, 2009 ) and in conditional Speg knockout (Speg-KO) mice ( Huntoon et al, 2018 ).…”

“…These findings are consistent with the fact that Speg deficiency in the skeletal muscle compartment results in abnormal triad development (formed by transverse tubules and sarcoplasmic reticulum), and faulty calcium handling and excitation-contraction coupling ( Huntoon et al, 2018 ). In the present study we assessed cardiac function in the small cohort of Speg −/− mice that survived to adulthood ( Liu et al, 2009 ) and in conditional Speg knockout (Speg-KO) mice ( Huntoon et al, 2018 ). The striated-muscle specific disruption of the gene allowed us to circumvent problems related to embryonic and perinatal mortality.…”

“…To evaluate cardiac function, we also assessed striated muscle specific Speg-KO mice on a C57BL/6 genetic background (mean 8.8 weeks of age). Speg-KO mice were created using a cre-loxP strategy, targeting exons 14–17 of Speg ( Huntoon et al, 2018 ). Floxed Speg mice were bred with mice expressing cre driven by the muscle creatinine kinase (MCK) promoter to generate Speg-KO mice.…”

Novel SPEG variant cause centronuclear myopathy in China

“…It was discovered in a mouse that SPEG dysfunction produces a myopathy by affecting Ca 2+ current function of the voltage sensor, calcium release from the SR and consequently reducing muscle contractility. 24,25 Recent studies confirmed that the protein kinase domain II is actually the key domain that controls the Ca 2+ re-uptake through regulating SERCA2a. 26 These indicate that dysfunction of protein kinase domain II of SPEG may cause CNM because of unbalanced calcium homeostasis through the SERCA2a pathway.…”

“…These can explain most genotype‐phenotype correlations of the patients. It was discovered in a mouse that SPEG dysfunction produces a myopathy by affecting Ca 2+ current function of the voltage sensor, calcium release from the SR and consequently reducing muscle contractility . Recent studies confirmed that the protein kinase domain II is actually the key domain that controls the Ca 2+ re‐uptake through regulating SERCA2a .…”