SUMMARYSarcomeres, 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.
Multimodal MRI and 31P-MRS Investigations of the ACTA1(Asp286Gly) Mouse Model of Nemaline Myopathy Provide Evidence of Impaired In Vivo Muscle Function, Altered Muscle Structure and Disturbed Energy Metabolism