Multiple muscular dystrophies interfere with muscle cholesterol homeostasis, causing muscle wasting similar to statin-associated myopathies, suggesting cholesterol-targeting therapies may help.
Muscular dystrophies may fundamentally be cholesterol-handling diseases, providing a mechanistic rationale for testing cholesterol-lowering medications to mitigate muscle wasting.
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ABSTRACT Background Muscular dystrophies (MD) are a genetically diverse group of muscle disorders, many of which arise from mutations in genes encoding components of the sarcolemma dystrophin‐associated glycoprotein complex (DGC). Despite their notorious heterogeneity, MDs consistently lead to chronic myofiber weakening, necrosis and loss of muscle mass, yet few unifying molecular pathways have been identified to explain this shared pathology. Methods In light of recent findings characterizing muscle symptoms in limb‐girdle MD recessive 28 (LGMDR28) – a condition caused by mutations to the rate‐limiting cholesterol synthesis enzyme and statin target 3‐hydroxy‐3‐methyl‐glutaryl‐coenzyme A reductase (HMGCR) – we summarize 4 decades of robust evidence describing how muscle ‘cholesterol depletion’ causes statin‐associated myopathies (SAM), which range from mild hyperCKmia to life‐threatening rhabdomyolysis during hypercholesterolemia management. After discussing myopathies caused by variants to 2 additional cholesterol pathway enzymes, we examine emerging data depicting circulating cholesterol abnormalities, muscle ‘cholesterol overload’ and lysosomal defects in multiple forms of rodent and human MD including Duchenne muscular dystrophy (DMD). Results When taken in combination with evidence showing extreme exacerbation of the notoriously mild phenotypes of dystrophin‐deficient mdx and dysferlin‐deficient mice by hypercholesterolemia, therapeutic responses to simvastatin and cholesterol absorption blocker ezetimibe in pre‐clinical studies, these findings suggest that multiple forms of MD may interfere with muscle cholesterol homeostasis to cause muscle wasting, akin to statins. Conclusions Further causal and mechanistic evidence of MDs being cholesterol‐handling diseases may ultimately lead to the counter‐intuitive testing of statins, ezetimibe and other cholesterol medications in certain MD populations and shed light on the muscle side‐effects of the most‐widely prescribed drug class.
Kang et al. (Thu,) reported a other. Multiple muscular dystrophies interfere with muscle cholesterol homeostasis, causing muscle wasting similar to statin-associated myopathies, suggesting cholesterol-targeting therapies may help.