Quadriceps myopathy caused by skeletal muscle-specific ablation of βcyto-actin

Abstract

Quadriceps myopathy (QM) is a rare form of muscle disease characterized by pathological changes predominately localized to the quadriceps. Although numerous inheritance patterns have been implicated in QM, several QM patients harbor deletions in dystrophin. Two defined deletions predicted loss of functional spectrin-like repeats 17 and 18. Spectrin-like repeat 17 participates in actin-filament binding, and thus we hypothesized that disruption of a dystrophin–cytoplasmic actin interaction might be one of the mechanisms underlying QM. To test this hypothesis, we generated mice deficient for βcyto-actin in skeletal muscles (Actb-msKO). Actb-msKO mice presented with a progressive increase in the proportion of centrally nucleated fibers in the quadriceps, an approximately 50% decrease in dystrophin protein expression without alteration in transcript levels, deficits in repeated maximal treadmill tests, and heightened sensitivity to eccentric contractions. Collectively, these results suggest that perturbing a dystrophin–βcyto-actin linkage decreases dystrophin stability, which results in a QM, and implicates βcyto-actin as a possible candidate gene in QM pathology.

Differential Actin-regulatory Activities of Tropomodulin1 and Tropomodulin3 with Diverse Tropomyosin and Actin Isoforms

“…In skeletal muscle fibers, Tmod1 caps the pointed ends of the skeletal muscle ␣-actin (␣ sk -actin) that polymerizes into the sarcomeric thin filaments, whereas Tmod3 is associated with the cytoplasmic ␥-actin (␥ cyto -actin) that polymerizes into the SR-associated membrane skeleton (7). Skeletal muscle fibers also contain a costamere-associated cytoplasmic ␤-actin network (29), although which Tmod isoforms (if any) associate with this network remain unknown. The segregation of Tmod1 versus Tmod3 with sarcomeric ␣ skactin filaments versus SR-associated ␥ cyto -actin filaments, respectively, suggests that Tmod1 and Tmod3 may exhibit different capping activities for the pointed ends of TM-coated ␣ sk -actin filaments as compared with ␤-actin or ␥ cyto -actin filaments.…”

Actin in striated muscle: recent insights into assembly and maintenance

“…Recent data from knockout animals for beta-and gamma-cytoplasmic actin from the Ervasti laboratory have ruled out their role in myofibrillogenesis, but established their importance for at least skeletal muscle function (Prins et al 2011;Sonnemann et al 2006). Currently, there exist slightly divergent reports on the localisation and expression levels of cytoplasmic actin isoforms in muscle (Kee et al 2009).…”

“…Actin is shown in red, the troponin complex in yellow and tropomyosin in grey vinculin localisation, a marker protein for costameres (Pardo et al 1983). On the other hand, the lack of beta-cytoplasmic actin in skeletal muscle does have an effect on dystrophin stability, but also leaves the overall costamere structure relatively unperturbed (Prins et al 2011). Several cytoplasmic actins, and also their associated proteins such as cytoskeletal tropomyosins and tropomodulin isoforms, have been localised to a compartment termed Z-LAC (Z-line adjacent cytoskeleton) in skeletal muscle (Kee et al 2009).…”

The sarcoplasmic reticulum

“…7 In contrast, the inner face of the sarcolemma contains a combination of nonmuscle actin isoforms: cytoplasmic β-actin (β cyto -actin) and cytoplasmic γ-actin (γ cyto -actin). 8,9 Our laboratory recently discovered that the SR is similar to the sarcolemma in that it also contains γ cyto -actin, 10 although whether β cyto -actin coexists with γ cyto -actin in the SR remains undetermined. (A second γ-actin isoform, smooth muscle γ-actin, is not expressed in skeletal muscle.…”

“…Furthermore, by analogy to Tmod-capped actin filaments at the cell membranes of RBCs, lens fiber cells and epithelial cells, Tmods may also function in capping and stabilizing β cyto -actin and γ cyto -actin filaments along the inner face of the sarcolemma. 8,9,18 These possibilities require further exploration.…”