Identification of deregulated AMPK and mTORC1 signalling in myotonic dystrophy type I and their potential as therapeutic targets

Myotonic Dystrophy type I (DM1) is a disabling multisystemic disease affecting skeletal muscle. The disease is caused by expanded (CTG)n repeats in the 3’UTR of the DMPK gene. (CUG)n-RNA-hairpins formed by the elongated transcripts lead to sequestration of splicing factors, and thereby to mis-splicing of various genes. Although different strategies have been tested to limit splicing defects, no causal treatment is available for this debilitating disease. To better understand the pathophysiology underlying the disease, we analysed whether DM1-associated muscle alterations may be related to a deregulation of central metabolic signalling and/or of the autophagy process in muscle. Although muscle atrophy in DM1 has been previously related to altered signalling and perturbation in catabolic processes, in-depth investigations into these areas are lacking. We showed that muscles from HSALR mice, a well-characterized mouse model for DM1, exhibit a defective response to energy restriction. Mutant muscles reveal blunted AMPK activation under staved conditions, which might be related to splicing-dependent CaMKII deficiency. Additionally, active mTORC1 signalling is maintained in muscle from starved mutant mice, while Akt is efficiently inhibited. We further observed that autophagy flux is impaired in HSALR muscle, which may arise from the deregulation of AMPK-mTORC1 signalling; autophagy is even more severely affected in human DM1 myotubes. Most importantly, normalization of these pathways with pharmacological or dietary approaches improved skeletal muscle strength and significantly reduced myotonia in HSALR mice. In particular, the AMPK agonist, AICAR, but not metformin, another drug known to induce the AMPK pathway, led to a marked amelioration of the relaxation time of mutant muscle, together with partial splicing correction of CLCN1. On the other hand, rapamycin, an mTORC1 inhibitor, and enduring low-protein diet, both reduced myotonia but not DM1-related mis-splicing. Furthermore, mTORC1 inhibition increases muscle force in HSALR mice. Taken together, this suggests that splicing-dependent as well as alternative, splicing-independent mechanisms can improve muscle function in DM1. These findings highlight the involvement of AMPK-mTORC1 imbalance in the disease and illustrate the importance of deregulated cellular processes contributing to DM1 muscle pathophysiology. At the same time this opens new avenues regarding therapeutic options for DM1, by modulating alternative processes aside from RNA toxicity.