What is the extent of autophagy suppression in muscular dystrophy?

Autophagy Suppression in Muscular Dystrophy

Autophagy is severely impaired in muscular dystrophy, with evidence showing persistent activation of autophagy-inhibiting pathways, downregulation of autophagy-inducing genes, and accumulation of damaged organelles. 1

Molecular Mechanisms of Autophagy Suppression

• Autophagy is a crucial cellular process for maintaining skeletal muscle health and function, involving the degradation of unnecessary or dysfunctional cellular proteins and organelles 2
• In Duchenne muscular dystrophy (DMD), there is persistent activation via phosphorylation of Akt, mammalian target of rapamycin (mTOR), and their dependent autophagy-inhibiting pathways 1
• Specific autophagy-inducing genes including LC3, Atg12, Gabarapl1, and Bnip3 are downregulated in muscular dystrophy 1
• The Akt axis is one of the key dysregulated pathways in DMD pathogenesis related to dysfunctional autophagy 2

Evidence of Autophagy Impairment

• Autophagy impairment occurs independent of disease progression, as demonstrated by similar patterns of dysfunction in both young (7-week-old) and aged (17-month-old) dystrophic diaphragms 3
• P62 protein, an inverse correlate of autophagic degradation, is dramatically elevated in dystrophic muscle regardless of age, indicating persistent impairment of autophagic flux 3
• Lysosomal marker Lamp2 shows a twofold decrease in dystrophic muscle at 17 months of age, suggesting lysosomal dysregulation contributes to autophagy impairment 3
• Autophagosome-sized p62-positive foci have been observed in the extracellular space of dystrophic muscle, indicating abnormal autophagosome processing 3

Consequences of Impaired Autophagy

• The defective autophagy leads to accumulation of damaged organelles in muscles from both DMD patients and mdx mice (a model of the disease) 1
• Autophagosome clearance (autophagy flux) does not increase to match the burden of accumulating damaged proteins and organelles after muscle fiber damage, creating a bottleneck effect 4
• This bottleneck effect results in reduced regenerative capacity marked by inadequate activation of muscle stem cells and lesser commitment toward differentiation 4
• The impaired autophagy contributes to muscle inflammation, fibrosis, and myofiber damage, ultimately affecting muscle function 1

Potential Therapeutic Approaches

• Long-term exposure to a low-protein diet has been shown to rescue defective autophagy in mdx mice by normalizing Akt and mTOR signaling 1
• Simvastatin treatment has demonstrated decreased CYBB/NOX2-mediated oxidative stress and enhanced autophagy induction in mdx mice 5
• Enhanced autophagy through simvastatin treatment was accompanied by reduced muscle damage, inflammation, fibrosis, and increased muscle force production 5
• Identifying molecular mechanisms governing autophagy and autophagy flux may serve as targets for future therapies to enhance recovery of muscle function in both healthy and diseased muscle 4

Clinical Implications

• Muscular dystrophy should be included in the differential diagnosis in patients presenting with proximal muscle weakness and elevated muscle enzyme levels 6
• Muscle biopsy can help distinguish muscular dystrophy from other neuromuscular diseases through histopathologic features such as reduction or absence of dystrophin with degenerating and regenerating muscle fibers 6
• Genetic testing for muscular dystrophy should include testing for the dystrophin gene 6
• The identification of autophagy impairment provides a new potential therapeutic target for DMD, which currently has no curative treatment 2, 1