Perhaps the first evidence of AMPKs therapeutic ability

Perhaps the first evidence of AMPKs therapeutic ability in DM1 came from Thomas Cooper’s laboratory where they demonstrated that insulin-independent glucose uptake was unaffected in human DM1 muscle CZC-25146 synthesis treated with MET, an AMPK activator and first-line therapy for type 2 diabetes mellitus [76]. Subsequently, case reports have found MET to be an effective treatment for combatting insulin resistance in DM1 patients [77]. Unfortunately, similar to the study noted above by Savkur and colleagues [76], skeletal muscle AMPK activation status was not assessed in these MET treatment scenarios. Nonetheless, these data support the concept that AMPK stimulation forms part of a compelling strategy for improving insulin resistance and glucose metabolism in DM1 (Figure 3C). Recent, preclinical studies clearly demonstrate a role for AMPK activation in DM1-associated alternative mRNA splicing 78, 79. Laustriat et al.[79] observed that AICAR was effective at evoking alternative splicing of numerous transcripts in DM1 cells. However, AICAR did not modulate the missplicing of the insulin receptor, whereas MET treatment was able to. This suggests agonist-specific effects on normalizing adult splicing patterns germane to DM1 [79]. There is evidence to suggest that AMPK might control alternative splicing of mRNAs via a mechanism involving its downstream target PGC-1α (Figure 3C). Though traditionally viewed as a transcriptional coactivator, PGC-1α also regulates RNA processing. Indeed, Monsalve and colleagues observed in skeletal muscle cells that PGC-1α associates with, and alters the activities of, splicing factors and RNA polymerase II during both the mRNA initiation and elongation phases, while Martínez-Redondo et al. engineered skeletal muscle-specific PGC-1α transgenic animals that demonstrated alternative splicing reactions mediated by the coactivator in vivo80, 81. Alternatively, AMPK may regulate mRNA alternative splicing via the RBP RNA-binding motif protein 3 (RBM3) [79]. However, these in vitro results were not recapitulated in DM1 mice treated with AICAR. Another possibility is that AMPK-regulated alternative splicing involves the dispersal of nuclear CUG foci [78] (Figure 3C). This process may be mediated by AMPKs inhibition of heterogeneous nuclear ribonucleoprotein H (hnRNP H) 82, 83. Here, nuclear AMPK interacts with hnRNP H, which reduces the stability of the expanded repeat tract, facilitating its export and thus potential liberation of MBNL1 from myonuclear foci 82, 83. This pathway would, in part, explain the mechanism for AMPKs control of alternative splicing in DM1, likely complementary to the kinases influence on RBM3 and/or PGC-1α. AMPK also has the potential to address the perturbed autophagic flux that remains a hallmark of the DM1 myopathy 78, 84. It is well known that AMPK plays a critical role in the initiation of autophagy by governing the function of ULK-1 [85]. Furthermore, AMPK also evokes autophagy-specific gene expression through transcriptional activation of autophagy-inducing factor Forkhead box O3 [85]. Thus, correcting upstream signaling in the autophagic cascade, perhaps at the level of AMPK, as well as by inducing the autophagy machinery, may be effective loci for therapeutic intervention to mitigate the DM1 myopathy (Figure 3C). Additional investigations that expand our knowledge of the mechanisms by which AMPK positively affects insulin sensitivity and glucose metabolism, mRNA processing, and alternative splicing, as well as autophagy in DM1 muscle are certainly warranted.
Exercise-Induced AMPK Activation in NMDs When employing informed principles of exercise prescription and optimal logistical criteria, the beneficial effects of maintaining physical activity levels in DMD, SMA, and DM1 patients are clearly revealed 86, 87, 88, 89. This must be considered within a broader perspective, one that acknowledges that the window of opportunity for physical activity for those with NMDs may be narrow and extreme care must be taken so as to not exacerbate the pathology. For instance, Jansen and colleagues [86] demonstrated that 24 weeks of assisted bicycle training was a safe and feasible method to mitigate functional decline in DMD patients. Furthermore, Madsen et al.[87] demonstrated that VO2max of adult SMA type III participants was enhanced with 12 weeks of moderate-intensity cycling exercise without increasing muscle damage, while Lewelt and coauthors [88] observed improvements in strength and motor function after progressive resistance training in children with types II and III SMA. The use of caution was urged during the prescription of exercise in SMA patients, as training was shown to induce significant fatigue [87]. Exercise studies with NMD participants are supported by many preclinical and mechanistic investigations of exercise biology in DMD and SMA models that also demonstrate safety and efficacy 59, 60, 90, 91. Importantly, single and repeated bouts of exercise are indeed effective at stimulating AMPK activation in NMD mice 92, 93. Thus, it is reasonable to suspect that chronic exercise-induced stimulation of AMPK drives some of the favorable adaptations in αMNs, NMJ, and myofibers in DMD, SMA, and DM1 via the various pathways described above. As NMD patients adopt novel contemporary therapies such as ASOs, and as proposed experimental approaches rapidly progress, these individuals will undoubtedly exhibit prolonged health and life spans. It is very likely, and indeed encouraged [31] therefore, that people with NMDs will embrace more active lifestyles that incorporate exercise prescriptions. Thus, there is a critical need to expand our understanding of the effects of acute exercise and chronic training in the DMD, SMA, and DM1 contexts. Included therein is whether exercise-induced AMPK activation may be used as an adjuvant of pharmacological treatments for NMDs, or vice versa [90].