SPEG-deficient Skeletal Muscles Exhibit Abnormal Triad and Defective Calcium Handling

Overview

Journal Hum Mol Genet

Specialties Genetics
Molecular Biology

Date 2018 Feb 24

PMID 29474540

Citations 19

Authors

Virginia Huntoon

Jeffrey J Widrick

Colline Sanchez

Samantha M Rosen

Candice Kutchukian

Siqi Cao

Christopher R Pierson

Xiaoli Liu

Mark A Perrella

Alan H Beggs

Vincent Jacquemond

Pankaj B Agrawal

Affiliations

Soon will be listed here.

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.

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