Satellite cells fail to contribute to muscle repair but are functional in Pompe disease (glycogenosis type II)

Abstract

Pompe disease, which is due to acid alpha-glucosidase deficiency, is characterized by skeletal muscle dysfunction attributed to the accumulation of glycogen-filled lysosomes and autophagic buildup. Despite the extensive tissue damages, a failure of satellite cell (SC) activation and lack of muscle regeneration have been reported in patients. However, the origin of this defective program is unknown. Additionally, whether these deficits occur gradually over the disease course is unclear. Using a longitudinal pathophysiological study of two muscles in a Pompe mouse model, here, we report that the enzymatic defect results in a premature saturating glycogen overload and a high number of enlarged lysosomes. The muscles gradually display profound remodeling as the number of autophagic vesicles, centronucleated fibers, and split fibers increases and larger fibers are lost. Only a few regenerated fibers were observed regardless of age, although the SC pool was preserved. Except for the early age, during which higher numbers of activated SCs and myoblasts were observed, no myogenic commitment was observed in response to the damage. Following in vivo injury, we established that muscle retains regenerative potential, demonstrating that the failure of SC participation in repair is related to an activation signal defect. Altogether, our findings provide new insight into the pathophysiology of Pompe disease and highlight that the activation signal defect of SCs compromises muscle repair, which could be related to the abnormal energetic supply following autophagic flux impairment.

Enzyme Replacement Therapy Can Reverse Pathogenic Cascade in Pompe Disease

“… 67 Similarly, a relatively slow rate of glycogen buildup in skeletal muscle of KO mice was demonstrated by us and others. 26 , 68 …”

Gene therapy with secreted acid alpha-glucosidase rescues Pompe disease in a novel mouse model with early-onset spinal cord and respiratory defects

“…The upregulation of several caspases such as 1, 3, and 6 in skeletal muscle also suggests the activation of a degenerative/regenerative process, as reported in other forms of muscular dystrophy [65] . Recent studies reported that in PD mice the upregulation of genes associated with muscle regeneration is accompanied to a low number of regenerating myofibers due to reduced activation of muscle satellite cells [66] . Interestingly, in the present study transcriptomic analyses of Gaa KO skeletal muscle showed an important downregulation of Klotho , whose deficiency has been linked to impaired muscle regeneration due to defects in muscle progenitor cells [67] .…”

Pompe Disease: New Developments in an Old Lysosomal Storage Disorder

“…These data provided indirect evidence of a failure of satellite cell activation in Pompe disease. In the follow-up studies in murine models of Pompe disease, two independent groups [98,99] demonstrated that despite extensive muscle damage, the number of regenerating fibers in adult animals is essentially negligible. Remarkably, the satellite cells were fully functional and were able to robustly respond to acute and repeated muscle injury induced by cardiotoxin or barium chloride leading to efficient muscle regeneration comparable to that in WT controls.…”