Disruptions of cell signaling pathways in myotonic dystrophy type 1 skeletal muscle, their pathogenic impact, and potential for combinatorial therapeutics.

Myotonic dystrophy type 1 (DM1) is caused by a CUG expansion located in the 3' UTR of dystrophia myotonica protein kinase mRNAs. The pathogenic model underlying DM1 implicates the accumulation of mutant dystrophia myotonica protein kinase transcripts in nuclei where they form toxic RNA foci. This, in turn, disrupts the availability of RNA-binding proteins causing widespread missplicing of mRNAs. Over the years, multiple signaling pathways have also been reported to be disrupted in DM1, especially in skeletal muscle. Here, we focus on several pathways including protein kinase R, PKC, glycogen synthase kinase 3β, Akt-mTOR, AMP-activated protein kinase, TWEAK-Fn14 and NF-κkB, and calcineurin-NFAT. We describe the individual effects of these signaling disruptions on multiple muscle functions and characteristics, and we also present an overview of their cumulative impact. Based on the available literature, dysregulation of signaling in muscle jointly results in global perturbations in protein synthesis and degradation, muscle repair, mitochondrial biogenesis, energy metabolism, and inflammation. The fact that pharmacological, physiological, and transgenic approaches targeting these pathways corrected defects observed in DM1 muscle provides a strong rationale for therapeutic intervention. These pathways can be targeted individually or through combinatorial treatments involving two or more agents. Based on the impact of these signaling pathways on multiple aspects of the DM1 muscle phenotype, therapeutically targeting these disruptions is becoming increasingly attractive and represents a critical area for additional research in the quest to slow or reverse muscle dysfunction in DM1.