Essential Role of Septin 7 in Skeletal Muscle Structure and Function

Abstract

Septins as components of the cytoskeleton have been shown to play an important role in various cellular processes, including cell mobility, apoptosis, and determining cell shape within a wide range of organisms. 13 human septins have been classified into 4 subgroups, where septin 7 is the only member of its group and is crucial in the formation of higher-order structures as filaments and rings. As limited information is available on septins in skeletal muscle, here the effect of downregulating septin 7 expression on skeletal muscle was examined. Cytoplasmic distribution of septin 7 in cultured myoblast, myotubes, and enzimatically isolated individual muscle fibers was investigated and its distribution was compared to the pattern of well-known proteins as α-actinin and ryanodine receptors. Septin 7 expression was modified both in cell culture and in mouse muscle fibers. In septin 7 knockdown (KD) C2C12 cells the parameters describing cellular shape and size were highly modified and cell proliferation and differentiation were suppressed. The reduced septin 7 expression caused severe vertebra deformity, similar to human Scheuermann's disease. In vivo and in vitro force measurements were carried out on septin 7 KD mice and muscles and significant reduction in the contractile parameters (Grip force, twitch, and tetanus) were observed. Voltage activation of calcium transients was examined on enzymatically isolated single FDB fibers under whole cell voltage clamp. Results indicate that the reduced expression of septin 7 does not alter the release channel activation significantly and the ECC machinery remains unaltered and fully operational in the mutant. These finding in skeletal muscle indicate that septin 7 has essential role in the development and differentiation process of myotubes and in proper function of adult skeletal muscle fibers. The research was supported by NKFIH K-115461 and GINOP-2.3.2-15-2016-00044.