The protein TDP-43, commonly implicated in neuromuscular diseases such as amyotrophic lateral sclerosis (ALS) and thought to be pathogenic, is shown to accumulate and have a functional role in normal muscle growth and regeneration, reports a paper published online this week in Nature. The authors suggest that increased muscle regeneration in disease may drive harmful accumulation of this protein.
Aggregates of TDP-43 protein accumulate in the skeletal muscles of patients with neuromuscular diseases such as inclusion body myopathy. Reducing TDP-43 levels leads to age-related muscle weakness in mice and Drosophila - suggesting that TDP-43 may have a functional role in muscle formation.
Roy Parker, Brad Olwin, and colleagues investigated TDP-43 function during normal mammalian skeletal-muscle formation. They find that it is abundant in mouse muscle cells, and levels increase during skeletal-muscle cell formation. Genetically depleting TDP-43 prevents cell growth and leads to cell death, suggesting an important functional role for this protein in muscle regeneration. Additionally, the authors report that during mouse muscle cell growth TDP-43 proteins assemble to adopt a more complex structure, called ‘myo-granules’, which can transition to an amyloid-like structure over time but are typically cleared in mature cells with normal function. Biopsies from patients with muscle weakness confirm the sustained presence of myo-granules in regenerating muscle.
The authors suggest that sustained muscle regeneration in neuromuscular disease may increase levels of TDP-43, and that failure to clear the resulting myo-granules may lead to the pathogenic amyloid-like accumulations seen in diseased muscles. Age-related factors may increase the risk of this transition occurring.