Cofilin loss inDrosophilacontributes to myopathy through defective sarcomerogenesis and aggregate formation during muscle growth

Abstract

Sarcomeres, the fundamental contractile units of muscles, are conserved structures composed of actin thin filaments and myosin thick filaments. How sarcomeres are formed and maintained is not well understood. Here, we show that knockdown of Drosophila Cofilin (DmCFL), an actin depolymerizing factor, leads to the progressive disruption of sarcomere structure and muscle function in vivo. Loss of DmCFL also results in the formation of sarcomeric protein aggregates and impairs sarcomere addition during growth. Strikingly, activation of the proteasome delayed muscle deterioration in our model. Further, we investigate how a point mutation in CFL2 that causes nemaline myopathy (NM) in humans, affects CFL function and leads to the muscle phenotypes observed in vivo. Our data provide significant insights to the role of CFLs during sarcomere formation as well as mechanistic implications for disease progression in NM patients.Thick filaments interact with thin filaments, and are crosslinked at the M-line, which is composed of proteins like obscurin (Henderson et al., 2017). While many conserved sarcomeric proteins have been identified, their incorporation into and function within the sarcomere are not completely understood. Moreover, it is still unclear as to how sarcomere size is regulated and maintained during muscle homeostasis. Understanding these fundamental areas of muscle biology is crucial, as mutations in sarcomeric proteins have been implicated in several muscle diseases.

Broiler genetics influences proteome profiles of normal and woody breast muscle

“…Cofilin-2 belongs to the actin depolymerization factor family and regulates actin filament dynamics ( Kanellos and Frame, 2016 ) while ACTA1 interacts with other proteins, specifically myosin, to produce force for muscle contraction. Thus, the decreased CFL2 and ACTA1 may indicate a weak muscle structure with decreased contractibility in strain 2 birds ( Balakrishnan et al., 2019 ). Moreover, strain 5 NB had a higher abundance of VDAC2 compared to strains 2 and 3.…”