Pharmacological and exercise-induced activation of AMPK as emerging therapies for myotonic dystrophy type 1 patients.

Myotonic dystrophy type 1 (DM1) is a multisystemic disorder with variable clinical features. Currently, there is no cure or effective treatment for DM1. The disease is caused by an expansion of CUG repeats in the 3' UTR of DMPK mRNAs. Mutant DMPK mRNAs accumulate in nuclei as RNA foci and trigger an imbalance in the level and localization of RNA-binding proteins causing the characteristic missplicing events that account for the varied DM1 symptoms, a disease mechanism referred to as RNA toxicity. In recent years, multiple signalling pathways have been identified as being aberrantly regulated in skeletal muscle in response to the CUG expansion, including AMPK, a sensor of energy status, as well as a master regulator of cellular energy homeostasis. Converging lines of evidence highlight the benefits of activating AMPK signalling pharmacologically on RNA toxicity, as well as on muscle histology and function, in preclinical DM1 models. Importantly, a clinical trial with metformin, an activator of AMPK, resulted in functional benefits in DM1 patients. In addition, exercise, a known AMPK activator, has shown promising effects on RNA toxicity and muscle function in DM1 mice. Finally, clinical trials involving moderate-intensity exercise also induced functional benefits for DM1 patients. Taken together, these studies clearly demonstrate the molecular, histological and functional benefits of AMPK activation and exercise-based interventions on the DM1 phenotype. Despite these advances, several key questions remain; in particular, the extent of the true implication of AMPK in the observed beneficial improvements, as well as how, mechanistically, activation of AMPK signalling improves the DM1 pathophysiology.