Muscle weakness revisited
Skeletal and cardiac muscles have a distinct structure known as the sarcomere, which is responsible for a muscle's ability to contract. Accumulating evidence indicates that the signalling functions of the sarcomere are partly mediated by two of its key proteins, titin and nebulin. Impaired muscle contractility is a frequently observed phenomenon in various diseases. This impairment could be secondary, such as in the case of metabolic disorders or chronic heart failure, or could be the direct cause of physical inactivity. Taken together, these observations portray a complex interconnection between muscle activity state, metabolism, life style and chronic disease, calling for further investigation. Scientists in the EU-funded SARCOSI(opens in new window) (Sarcomere based signals in muscle remodelling) project set out to understand how impaired muscle contractility develops in disease states and how this further contributes to pathology. The consortium consisted of multidisciplinary research teams and clinical experts in the field from Brazil, Japan and the United States. Special focus was given to the role of nebulin, which is critical for maintaining sarcomere structure and myofibril force production. The consortium studied patients with nemaline myopathy, a condition where they lack the protein nebulin. The researchers identified several mutations in the nebulin gene that are implicated in this condition. Based on this, they established mouse models that carried these mutations and successfully identified molecular biomarkers. Valid for human nemaline myopathy diagnosis, these biomarkers can be used to test the efficacy of potential drug compounds in restoring muscle function. Collectively, the SARCOSI initiative has resulted in a permanent platform for joint international research projects on conditions associated with pathological muscle remodelling. Given the increasing incidence of obesity and rise in ageing population, further research should aid in the development of novel solutions for pathological muscle restructuring and wasting.
