Institut NeuroMyoGène, Physiopathologie et Génétique du Neurone et du Muscle, Univ. Lyon 1, FRANCE
AMPK activation improves skeletal muscle homeostasis in dystrophies
Host: S. Zacchigna
Abstract
Degenerative myopathies are characterized by permanent muscle tissue injuries, chronic inflammation and fibrosis. Fibrosis and chronic inflammation are important pathological aspects in Duchenne Muscular Dystrophy (DMD) and represent barriers lowering the efficacy of gene therapy envisaged for correcting the genetic defect causing the pathology. We demonstrated that on the contrary to regenerating healthy muscles, the resolution of inflammation is impaired in DMD muscles, with the presence of a specific population of pro- inflammatory/profibrotic macrophages. We showed that the activation of the metabolic regulator AMPK is beneficial for muscle homeostasis, by inducing the resolution of inflammation by macrophages, leading to a significant improvement of muscle function in the mouse. This identifies the macrophage inflammatory shift as a relevant therapeutic target in DMD. However, efficient molecules for this purpose may have a broad impact and be toxic. Our approach is to design novel treatments based on specific targeting of small molecules to muscular macrophages to induce the regenerative inflammation in DMD muscle. Our results show that encapsulated AMPK allosteric activators inhibit fibrotic macrophage properties in vitro and in vivo in the DMD mouse model without adverse effects, establishing the proof of concept of their use.
International Seminar Programme
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