Determinants of muscle regeneration

Muscular dystrophy is a progressively debilitating group of genetic disorders that eventually cause the muscles to weaken. The onset of disease varies and so does the outcome, ranging from an inability to walk to breathing problems. Currently there is no cure for muscular dystrophies and interventions only treat the symptoms.

A more recent treatment uses general inhibitors of the histone deacetylase (HDAC) enzyme that usually functions to wrap the DNA more tightly and regulate gene transcription. The main aim of the EU-funded MUSCLE REPAIR MDX (Molecular mechanisms involved in skeletal muscle repair and muscular dystrophy) project is to further define the functions of HDAC in muscle repair and muscular dystrophy. In this context, the consortium will follow a loss-of-function approach by genetically deleting the isoform 4 of HDAC (HDAC4) at different stages of muscle regeneration.

During the first part of the project, scientists have induced muscle damage in mice lacking HDAC4 in skeletal muscle and observed its regenerative capacity. Their results show that skeletal muscle from mice lacking HDAC4 regenerates less effectively than that of control mice following injury as their muscle stem cells cannot properly differentiate. Similarly, dystrophic mice lacking HDAC4 in skeletal muscle exhibit more damaged fibres and degenerating muscles than dystrophic mice.

Collectively, these results indicate that HDAC is an important factor in muscle regeneration. Considering that HDAC inhibitors are in use for the treatment of dystrophic patients, inhibition of HDAC activity may worsen muscle regeneration and muscular dystrophy and should, therefore, be revisited.