Determinants of muscle regeneration
Muscular dystrophy is a group of progressively debilitating 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 was to further define the functions of HDAC in muscle repair and muscular dystrophy. The consortium followed a loss-of-function approach by genetically deleting the isoform 4 of HDAC (HDAC4) at different stages of muscle regeneration. 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. Looking at the precursor to muscle cells, satellite cells, HDAC4 knock-out mice had less proliferation and could not differentiate in muscle lineage. Striking accumulation of fibrotic and adipose tissue was found after multiple muscle injury, stressing the important role HDAC4 plays in satellite cell pool maintenance. Molecular pathways affected by HDAC4 point to the genes involved in cell proliferation and redox balance in satellite cells. 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.
