Autophagy in skeletal muscle: implications for Pompe disease

Abstract

Pompe disease is caused by an inherited deficiency of acid a-glucosidase (GAA), a lysosomal enzyme that catalyzes the breakdown of glycogen to glucose. In the absence of GAA, enlarged, glycogen-laden lysosomes accumulate in multiple tissues, although the major clinical manifestations are seen in cardiac and skeletal muscle. For many years, it was believed that the rupture of glycogen-filled lysosomes was the major cause of the profound muscle damage observed in patients with Pompe disease. Here, we present evidence that a failure of productive autophagy in muscle tissue contributes strongly to disease pathology in both patients with Pompe disease and GAA-knockout mice. In the GAA-knockout mouse model, progressive accumulation of autophagic vesicles is restricted to Type II-rich muscle fibers. Not only does this build-up of autophagosomes disrupt the contractile apparatus in the muscle fibers, it also interferes with enzyme replacement therapy by acting as a sink for the recombinant enzyme and preventing its efficient delivery to the lysosomes. Our data indicate that a re-examination of the presumed pathological mechanism in Pompe disease is necessary, and suggest that successful treatment of patients with Pompe disease will require consideration of the dramatic failure of autophagy that occurs in this disease.

Figure 1

Electron micrographs of (a) Type I-rich (soleus) muscle and (b) Type II-rich (gastrocnemius) muscle from a 5-month-old acid α-glucosidase knockout mouse.

Figure 2

Differential interference contrast microscopy images of unstained single muscle fibers from (a) 6-month-old wild-type and (b) acid α-glucosidase (GAA)-knockout mice. Centrally located autophagic accumulation is clearly visible throughout the length of the fiber from the GAA-knockout mouse. Bar, 20 μm.

Figure 3

Western blot analysis of microtubule-associated protein 1 light chain 3 (LC3) in skeletal muscle derived from wild-type (WT) and acid α-glucosidase (GAA)-knockout (KO) mice. In KO mice, both Type I-rich (soleus) muscle and Type II-rich (gastrocnemius) muscle showed higher levels of LC3-I and LC3-II compared with WT. Muscle biopsies were taken from 5-month-old mice.

Figure 4

Toluidin blue-stained biopsies taken from Type-II rich extensor digitorum longus muscle of acid α-glucosidase knockout mice. a: 0.5-month-old mouse, b: 1-month-old mouse, c: 23-month-old mouse.