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

Abstract

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.

The bidirectional relationship between AMPK pathway activation and myokine secretion in skeletal muscle: How it affects energy metabolism

“…BDNF, ANGPTL4, FGF21, LIF, and myostatin have all been shown to be dysregulated in DMD, whereas literature suggests AMPK activation may yield positive effects against the disease by contributing to increased muscle function and inducing mitophagy. Upregulated IL-6 signalling, reduced plasma irisin, and impaired AMPK signalling have all been associated with myotonic dystrophy ( Dozio et al, 2017 ; Nakamori et al, 2017 ; Ravel-Chapuis et al, 2022 ). Some studies have shown that AMPK activation reduced myotonia, inhibited RNA toxicity, and enabled functional benefits via histological improvements, and therefore suggested targeted activation of AMPK signalling as a potential therapeutic approach ( Brockhoff et al, 2017 ; Ravel-Chapuis et al, 2022 ; Ravel-Chapuis and Jasmin, 2022 ).…”

“…Upregulated IL-6 signalling, reduced plasma irisin, and impaired AMPK signalling have all been associated with myotonic dystrophy ( Dozio et al, 2017 ; Nakamori et al, 2017 ; Ravel-Chapuis et al, 2022 ). Some studies have shown that AMPK activation reduced myotonia, inhibited RNA toxicity, and enabled functional benefits via histological improvements, and therefore suggested targeted activation of AMPK signalling as a potential therapeutic approach ( Brockhoff et al, 2017 ; Ravel-Chapuis et al, 2022 ; Ravel-Chapuis and Jasmin, 2022 ). As the full molecular mechanism of many of these pathways have yet to be elucidated, understanding myokine-AMPK interactions sheds some light on potential signalling pathways that may be leveraged in these investigations.…”

Studying the Effect of MBNL1 and MBNL2 Loss in Skeletal Muscle Regeneration

“…In addition to their roles as splicing factors, these proteins have a myriad of functions in RNA processing and localization [ 11 ]. There is also experimental evidence for other mechanisms involving transcription factors, signaling such as the glycogen synthase kinase 3-beta (GSK-3β), AKT, AMPK, PKC, Tweak/Fn14, PI3K/AKT pathways, other RNA binding proteins (e.g., hnRNPA1 and MSI2), circular RNA generation, microRNAs, mitochondrial dysfunction, increased cellular senescence, and most recently, calcium channel dysfunction in conjunction with chloride channel dysfunction [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ]. However, the strongest evidence is for the loss of function of MBNL proteins due to binding to the mutant RNA and their sequestration in the RNA foci [ 35 ].…”

A single dose of exercise stimulates skeletal muscle mitochondrial plasticity in myotonic dystrophy type 1

“…For example, interventions, such as exercise, designed to stimulate AMP-activated protein kinase (AMPK), are strong candidates to mitigate declines in muscular function and other clinical variables in several NMDs, including DM1. [21][22][23][24] AMPK is a master regulator of neuromuscular plasticity due, in part, to its regulatory roles in mitochondrial biology. 21 Indeed, a recent clinical trial demonstrated several physiological benefits in DM1 patients following 12 weeks of aerobic exercise training that was accompanied by augmented skeletal muscle mitochondrial content and respiration, as well as partially normalized expression of mitochondrial dynamics proteins.…”

“…Several therapies are being investigated to combat DM1 onset and progression. For example, interventions, such as exercise, designed to stimulate AMP‐activated protein kinase (AMPK), are strong candidates to mitigate declines in muscular function and other clinical variables in several NMDs, including DM1 21–24 . AMPK is a master regulator of neuromuscular plasticity due, in part, to its regulatory roles in mitochondrial biology 21 .…”