Abstract/Summary

Skeletal muscle loss is a feature of many human disease conditions. Importantly, maintaining muscle mass is a prognostic indicator of good health with local and systemic effects. Considerable research has been conducted to develop therapies for muscle-wasting conditions. One of the most attractive means to achieve this goal is through the inhibition of the myostatin/activin signalling pathway. Here, we hypothesise that the application of this approach would maintain skeletal muscle mass in a diverse range of rodent models for muscle wasting with different underlying causes, ranging from acute to chronic conditions: Sickle-Cell Disease, Duchenne Muscular Dystrophy, Limb-Girdle Muscular Dystrophy and Peritonitis. The study investigated the effects on body and skeletal muscle weights, functional and physiological parameters, skeletal muscle pathology and morphometrics, gene expression in skeletal muscle and off-target effects. Antagonising myostatin/activin signalling pathway did not affect the body weight of the rodent model for Sickle-Cell Disease, Duchenne Muscular Dystrophy and early stages of Limb-Girdle Muscular Dystrophy and Peritonitis. In contrast, the body weight of older Sgca-null mice was decreased while the body weight at the resolving stage of the Peritonitis model was increased. Furthermore, all rodent models increased skeletal muscle weight, except in the early stage of Peritonitis. The increased skeletal muscle weight was associated with muscle fibre hypertrophy in all rodent models. Functional analysis revealed an increased specific titanic force in D2.mdx mice but did not affect mdx mice, while the Sgca-null mice two limb hanging tests were decreased by myostatin/activin inhibition. No effect was observed in the functional parameters of the Peritonitis model. Off-target effects were observed in decreased splenomegaly in the Sickle-Cell Disease mouse model and a multi-organ weight decrease in the Duchenne Muscular Dystrophy mouse models (testes and kidneys). Therefore, in some but not all cases, myostatin/activin inhibition exhibited benefits but has limitations. Here, we propose that it is vital to understand the mechanisms underpinning muscle wasting via recent advances in spatial transcriptomics, as they may occur without the involvement of myostatin/activin signalling. Furthermore, we suggest combinational intervention may result in robust muscle growth where one arm involves myostatin/activin inhibition and the other a gene therapy.