Transgenic overexpression of γ-cytoplasmic actin protects against eccentric contraction-induced force loss in mdx mice

Abstract

Backgroundγ-cytoplasmic (γ-cyto) actin levels are elevated in dystrophin-deficient mdx mouse skeletal muscle. The purpose of this study was to determine whether further elevation of γ-cyto actin levels improve or exacerbate the dystrophic phenotype of mdx mice.MethodsWe transgenically overexpressed γ-cyto actin, specifically in skeletal muscle of mdx mice (mdx-TG), and compared skeletal muscle pathology and force-generating capacity between mdx and mdx-TG mice at different ages. We investigated the mechanism by which γ-cyto actin provides protection from force loss by studying the role of calcium channels and stretch-activated channels in isolated skeletal muscles and muscle fibers. Analysis of variance or independent t-tests were used to detect statistical differences between groups.ResultsLevels of γ-cyto actin in mdx-TG skeletal muscle were elevated 200-fold compared to mdx skeletal muscle and incorporated into thin filaments. Overexpression of γ-cyto actin had little effect on most parameters of mdx muscle pathology. However, γ-cyto actin provided statistically significant protection against force loss during eccentric contractions. Store-operated calcium entry across the sarcolemma did not differ between mdx fibers compared to wild-type fibers. Additionally, the omission of extracellular calcium or the addition of streptomycin to block stretch-activated channels did not improve the force-generating capacity of isolated extensor digitorum longus muscles from mdx mice during eccentric contractions.ConclusionsThe data presented in this study indicate that upregulation of γ-cyto actin in dystrophic skeletal muscle can attenuate force loss during eccentric contractions and that the mechanism is independent of activation of stretch-activated channels and the accumulation of extracellular calcium.

Interaction of α-Catulin with Dystrobrevin Contributes to Integrity of Dystrophin Complex in Muscle

“…Overexpression of utrophin protects mdx muscle from the disorganization of costameric actin. Similarly, overexpression of ␥-actin improves the dystrophic phenotype of mdx muscle (43). In this context, the increase of sarcolemmal ␣-catulin levels in mdx muscle may be a compensatory mechanism that has a role in protection from sarcolemmal damage.…”

Caspase-12 ablation preserves muscle function in the mdx mouse

“…For example, expression of a minidystrophin gene completely preserved EDL specific force, but only led to a 20% recovery in resistance to ECCs (41), while overexpression of the dystrophin homologue utrophin completely preserved specific force in EDL and diaphragm muscles, and resistance to ECCs in EDL (42). Overexpression of g-actin reduced susceptibility of the EDL to ECCs by 40% compared with mdx, but did not improve specific force (43). C57 controls were not included in this study, so percentage recovery could not be calculated.…”

Thromboxane-induced actin polymerization in hypoxic neonatal pulmonary arterial myocytes involves Cdc42 signaling

“…␥-Actin expression may be developmentally regulated; in late pregnancy, ␥-actin expression increases in uterine myocytes and may facilitate myometrial contraction (42). That ␥-actin promotes force development is supported by the observation that overexpression of cytoplasmic ␥-actin in thin filaments prevents loss of force during eccentric contraction of dystrophic skeletal muscle (2). In contractile aortic myocytes, adrenergic contraction results in a net polymerization of ␥-actin, which contributes toward agonist-induced tone without affecting KCl-mediated contraction (23).…”