Dysfunctional autophagy impairs muscle regeneration in lysosomal diseases

Lysosomal diseases are metabolic diseases which occur because of a deficiency of one of the essential lysosomal enzymes. A mutation in the gene encoding one of these enzymes leads to an accumulation of unwanted substrates, resulting in a variety of clinical manifestations. A common symptom found in lysosomal diseases is skeletal muscle dysfunction, which includes muscle weakness, atrophy and loss of muscle mass. One metabolic pathway which has been shown to be essential for maintenance of skeletal muscles is autophagy. This study sought to investigate the impact of lysosomal diseases on autophagy and how this may potentiate muscle dysfunction. We utilized in-vivo and in-vitro models of sialidosis, Sandhoff disease, and GM1-gangliosidosis to assess autophagy and its impact on myogenic differentiation in skeletal muscles. Our results demonstrated that in lysosomal diseases, autophagy is induced upstream, i.e., ULK1 phosphorylation but is hindered at the autophagosome to lysosome fusion step, i.e., p62 accumulation which led to impairment of myoblast fusion and myogenic differentiation. We conclude that blocking autophagy impairs myogenic differentiation, which potentiates the muscle dysfunction observed in lysosomal diseases. This work highlights autophagy as a new pathway of interest and possible therapeutic target to alleviate muscle dysfunction in lysosomal diseases.