A potentially new therapeutic target in Pompe disease

Pompe disease affects cardiac and skeletal muscle. Accumulation of glycogen, build up of autophagic material, and muscle atrophy are all well-described features. Enzyme replacement therapy has dramatically improved the outlook. However, it is not perfect.

Muscle atrophy can occur in the absence of glycogen build up and defective autophagy. The cause is not clear; the precise cell-signalling mechanisms involved have yet to be elucidated.

Interest has focused recently on mTOR (mechanistic target of rapamycin). This is a serine-threonine kinase that is a regulator of cell growth, including muscle mass. mTOR exists as two complexes, mTORC1 and mTORC2. Of these, mTORC1 is closely associated with the lysosome, where it is activated. Upon activation, it suppresses autophagy and facilitates cell growth and protein synthesis. A detailed discussion is beyond the scope of this post but please see this paper.

mTOR and lysosomal regulation

The close association of mTORC1 with the lysosome has led to speculation that it might be a useful therapeutic target in LSD’s. Now, teams from the National Institutes of Health and Boston have published the results of their systematic studies of mTOR activity in Pompe muscle cells. They have shown that mTOR activity is reduced, and that this is at least in part due to the action of tuberous sclerosis complex 2 (TSC2) (please see this link for a detailed discussion of TSC2). The group have further gone on to show that the effect of TSC2 on mTOR activity can be reversed by arginine. This effect was seen in vitro and, critically, in vivo; oral administration of arginine to Pompe mice resulted in clearing of autophagy and increased muscle mass. The full paper can be found here:-

Modulation of mTOR signaling as a strategy for the treatment of Pompe disease

Clearly there is a long way to go. The muscle atrophy seen in patients can be very severe, and there may well be a point beyond which nothing can reverse it. It is also unclear how effective such an intervention would be on its own in clinical practice.

However, at the very least, these are very interesting findings, in that they suggest that there may well be alternative approaches to the treatment of this devastating condition. The authors have made a strong case for clinical translation. They also very reasonably point out that, given the central regulatory role of mTOR in lysosomal function, other LSD’s may well stand to benefit from such approaches.


Author: Ashok Vellodi

I have had a lifelong interest in lysosomal storage disorders. Having recently retired I now have time to pursue my passion for teaching and training of young doctors and scientists, and hopefully instil in them the passion for their patients that is so integral to working in this field.

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