Suppression of autophagy permits successful enzyme replacement therapy in a lysosomal storage disorder—murine Pompe disease

TLDR

Autophagy, a system that delivers cytoplasm and damaged organelles to lysosomes for degradation, is disrupted in many diseases, including Pompe disease—a lysosomal storage disorder caused by deficient acid α‑glucosidase that leads to cardiac and skeletal muscle myopathy, where enzyme replacement therapy clears heart glycogen but not skeletal muscle. The study aims to eliminate autophagic debris in Pompe muscle by creating a mouse model with muscle‑specific deletion of the autophagy gene Atg7. They generated a Pompe mouse with muscle‑specific Atg7 knockout to suppress autophagy. Suppressing autophagy in these mice reduced muscle glycogen by 50–60 % alone and, when combined with enzyme replacement therapy, restored glycogen to normal levels—an effect not seen in mice with intact autophagy—suggesting autophagy inhibition as a promising therapeutic strategy.

Abstract

Autophagy, an intracellular system for delivering portions of cytoplasm and damaged organelles to lysosomes for degradation/recycling, plays a role in many physiological processes and is disturbed in many diseases. We recently provided evidence for the role of autophagy in Pompe disease, a lysosomal storage disorder in which acid alphaglucosidase, the enzyme involved in the breakdown of glycogen, is deficient or absent. Clinically the disease manifests as a cardiac and skeletal muscle myopathy. The current enzyme replacement therapy (ERT) clears lysosomal glycogen effectively from the heart but less so from skeletal muscle. In our Pompe model, the poor muscle response to therapy is associated with the presence of pools of autophagic debris. To clear the fibers of the autophagic debris, we have generated a Pompe model in which an autophagy gene, Atg7, is inactivated in muscle. Suppression of autophagy alone reduced the glycogen level by 50–60%. Following ERT, muscle glycogen was reduced to normal levels, an outcome not observed in Pompe mice with genetically intact autophagy. The suppression of autophagy, which has proven successful in the Pompe model, is a novel therapeutic approach that may be useful in other diseases with disturbed autophagy.