The SMN and SMN promoters are regulated by

The SMN1 and SMN2 promoters are regulated by transcription factors such as E26 transformation-specific domain containing protein (ELK-1) and cAMP response element-binding protein (CREB) 58, 59. Compared with WT animals, mice with SMA exhibit increased and decreased ELK-1 and CREB phosphorylation, respectively, in skeletal muscle and SC, concomitant with lower levels of FL-SMN protein PI3K Akt mTOR Compound Library 59, 60. Chronic activation of the N-methyl-d-aspartate receptor in SMA mice stimulated CREB activity and reduced ELK-1 phosphorylation in the SC, coincident with a significant upregulation of FL-SMN [59]. Although AMPK signaling was not measured in this study, it has previously been shown that AMPK phosphorylates CREB [61]. It is reasonable to hypothesize, therefore, that activating AMPK would result in FL-SMN induction, potentially via a CREB-mediated pathway (Figure 2C). Along these lines, chronic AICAR administration in SMA mice attenuated skeletal muscle atrophy and improved NMJ morphology [6]. However, AMPK activation was not able to stimulate FL-SMN expression or prevent αMN loss. Unfortunately, CREB expression or activity was not examined in this report, so it is still unknown whether activation of AMPK–CREB signaling is an effective strategy for FL-SMN induction. Nonetheless, the evidence indicates that a course of chronic pharmacological AMPK activation can elicit benefits to SMA mice in an SMN-independent manner. The NMJ dysfunction associated with SMA is myriad [54]. SMN-dependent transgenic and pharmacological technologies address NMJ defects by preserving synaptic integrity and morphology, as well as by restoring NMJ endplate transmission efficacy 57, 62. Normalization of the NMJ may also occur via SMN-independent means [63] (Figure 2C). Indeed, pharmacological stimulation of AMPK demonstrated protective effects on NMJ morphology and synaptic transmission in SMA mice without alterations in FL-SMN levels [6]. Samuel and colleagues [25] provide additional support for AMPK as a positive mediator of synaptic remodeling. Here, the authors demonstrated that AMPK signaling rescued synaptic dysfunction as a consequence of advanced aging, a condition that shares many similarities with SMA with respect to NMJ degeneration [64]. A mechanism that may explain the potential influence of AMPK on the NMJ is its signaling through PGC-1α, a master regulator of the NMJ gene program 23, 24. Increased AMPK activity could also lead to the upregulation of local trophic factors, like brain-derived neurotrophic factor for example [65], that would, in turn, improve NMJ biology in SMA. Mitochondrial dysfunction also contributes to the SMA pathology 66, 67. Interestingly, Miller and colleagues [66] observed mitochondrial abnormalities in αMNs of SMA mice at presymptomatic time points, suggesting that mitochondrial defects contribute to disease onset. Experimental therapies targeting mitochondria, such as olesoxime, which addresses organelle dysfunction via SMN-independent means, have shown promise in SMA patients [68]. This is advantageous since AMPK activation is a potent stimulus for driving mitochondrial biogenesis in skeletal muscle and neurons 19, 69 (Figure 2C). In preclinical models of NMDs, chronic pharmacological AMPK stimulation leads to enhanced mitochondrial biogenesis and function, coincident with attenuations in disease pathology 36, 46, 70. Thus, AMPK is poised to play an important role in SMN-dependent and SMN-independent therapeutic mechanisms in SMA.
AMPK in DM1 At about 1/8000 individuals, DM1 is the most prevalent adult form of muscular dystrophy, as well as the second most common type of muscular dystrophy after DMD 71, 72. It is an NMD with multisystem involvement, most prominently characterized by skeletal muscle weakness, wasting, myotonia, and insulin resistance. DM1 is caused by a CTG microsatellite repeat expansion mutation in the 3′ untranslated region (UTR) of the dystrophia myotonica protein kinase (DMPK) gene [71]. The expanded DMPK transcripts form stable double-stranded hairpin structures that aggregate in myonuclear foci. Via a toxic gain-of-function mechanism, these CUG expansions cause the deregulation of several important RBPs, namely, Muscleblind-like 1 (MBNL1) and CUG-BP, Elav-like family member 1 (CELF1, also called CUG-BP1; Figure 3A,B). Both CELF1 and MBNL1 play critical roles in many steps of RNA metabolism, including primarily pre-mRNA processing, as well as in the stability and transport of newly synthesized transcripts. MBNL1 becomes sequestered by the nuclear aggregates, which leads to MBNL1 loss of function, while CELF1 experiences an aberrant gain of function via protein kinase C-mediated phosphorylation 71, 72. The myotonia of DM1, for example, is largely attributed to the presence of the fetal isoform of the skeletal muscle-specific chloride channel (ClC-1), which is alternatively spliced due to the imbalance of MBNL1 and CELF1 activities [71] (Figure 3B). Prevalent experimental strategies in preclinical models of the disorder employ siRNA/small hairpin RNA or small molecule technologies to target DMPK transcript degradation by disrupting the MBNL1 and CUG repeat interaction, or by inhibiting the CUG expanded RNA, respectively 71, 73. ASOs also effectively attenuate MBNL1 myonuclear sequestration and splicing errors in cell cultures from DM1 patients, as well as in DM1 mice [74]. However, the effective systemic delivery of ASOs poses a significant technical challenge [75].