Clearance of lysosomal glycogen accumulation by Transcription factor EB (TFEB) in muscle cells from lysosomal alpha-glucosidase deficient mice

A recently proposed therapeutic approach for lysosomal storage disorders (LSDs) relies upon the ability of transcription factor EB (TFEB) to stimulate autophagy and induce lysosomal exocytosis leading to cellular clearance. This approach is particularly attractive in Glycogen Storage Disease type II (a severe metabolic myopathy and a paradigm for LSDs, also called Pompe disease) as the currently available therapy, replacement of the missing enzyme acid alpha-glucosidase, fails to reverse skeletal muscle pathology. Pompe disease is characterized by both lysosomal abnormality and dysfunctional autophagy. Here we show that TFEB is a viable therapeutic target in Pompe disease: overexpression of TFEB in a newly established conditionally immortalized skeletal muscle cell model reduced glycogen load and lysosomal size; and in the muscle fibers of GFP-LC3 Pompe disease mouse model significantly increased the motility of lysosomes in the fibers, and stimulated the fusion between lysosomes and autophagosomes under stress. Hence, modulation of TFEB activity holds promise for the development of a better therapy. In addition, the newly developed mouse and cell models have many potential applications such as large-scale drug screening for Pompe disease.