Disruptions of Cell Signaling Pathways in Myotonic Dystrophy Type 1 (DM1) 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' untranslated region (UTR) of dystrophia myotonica protein kinase (DMPK) mRNAs. The pathogenic model underlying DM1 implicates the accumulation of mutant DMPK transcripts in nuclei where they form toxic RNA foci. This, in turn, disrupts the functional availability of several RNA-binding proteins involved in pre-mRNA alternative splicing. Consequently, such dysregulations result in widespread missplicing of multiple mRNAs accounting for the plethora of DM1 symptoms. Accordingly, DM1 is referred to as a spliceopathy. Over the years, multiple signaling pathways have also been reported to be disrupted in DM1, especially in skeletal muscle. In this review, we focus on several of these pathways including protein kinase R (PKR), protein kinase C (PKC), glycogen synthase kinase 3β (GSK-3β), Akt-mTOR, AMP-activated protein kinase (AMPK), TWEAK-Fn14 and NF-kB, and calcineurin-NFAT. We describe the individual effects of these signaling disruptions on multiple skeletal muscle functions and characteristics, and we also present an overview of their cumulative impact. Based on the available literature, the dysregulation of signaling in skeletal muscle jointly results in global perturbations in protein synthesis and degradation, muscle repair, mitochondrial biogenesis, energy metabolism and inflammation. Despite these advances, the full spectrum of alterations in signaling pathways in DM1 muscle remains incomplete and a certain level of variability in the extent of signaling defects in DM1 muscles has been observed likely due to varied experimental approaches and designs. Additional key unanswered questions relate to how mechanistically the CUG expansion in DMPK mRNAs causes the dysregulation of multiple signaling cascades, and whether missplicing of pivotal signaling molecules within these various pathways further contributes to signaling defects. The fact that pharmacological, physiological, and transgenic approaches targeting these pathways have corrected defects observed in DM1 muscle provides a strong rationale for therapeutic intervention. These pathways can be targeted either individually or through combinatorial treatments involving two or more agents and/or strategies. Based on the importance and 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.