Muscle atrophy is a well-documented symptom of Huntington’s disease (HD) and there are multiple lines of evidence to support a muscle-based pathology in HD patients and in mouse models of HD. Inhibition of the myostatin signalling pathway has been shown to increase muscle mass and therapeutic approaches, which include the use of an ActRIIB receptor decoy and antibodies directed at the myostatin ligand, are in clinical development for a number of indications.

We have used an ActRIIB receptor decoy to test the effects of myostatin inhibition in the R6/2 mouse model of HD. We found that weekly administration from five weeks of age completely rescued the body weight loss, reduction in muscle mass (quadriceps, tibialis and gastrocnemius) and grip strength impairment during the expected life span of an R6/2 mouse and delayed end-stage disease by approximately 2 weeks. Treatment had no effect on rotarod performance or open field deficits suggesting that these behavioural phenotypes arise through centrally located pathogenic mechanisms. We have assessed neuromuscular function by determining the maximum twitch and tetanic force in the tibialis anterior and extensor digitorum longus (EDL) muscles and shown that treatment with the receptor decoy results in considerable restoration of the corresponding impairments. Similarly, the loss of motor units was completely restored in EDL muscles.

The R6/2 and HdhQ150 knock-in mice both develop a skeletal muscle-based aggregate pathology in the form of nuclear inclusions. Analysis by the Seprion ELISA indicates that the aggregate load is greater in tibialis as compared to quadriceps or gastrocnemius, and that this is reduced 12 weeks of age in all three muscle types in treated mice. We have quantified the expression level of a wide range of transcripts and whilst in the case of many genes, the level of dysregulation is less pronounced in the treated as compared to untreated mice, the pattern of dysregulation is complex and can differ between muscle types. Taken together, these molecular data suggest that ActRIIB receptor decoy treatment may have had disease modifying effects in skeletal muscle.

Knowledge of the safety and tolerability of the various myostatin inhibition modalities that are in clinical trials will drive future preclinical work to evaluate this as a potential therapeutic target for HD.