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    • The chronic induction of skeletal muscle AMPK activity

    2022-12-02

    The chronic induction of skeletal muscle AMPK activity is an attractive therapeutic approach for DMD, as it addresses multiple cellular pathways needed for powerful phenotypic plasticity, including activation of the slow oxidative myofiber program, corrective autophagic signaling, as well as regulation of myofiber regeneration (Figure 1C). These phenomena mitigate the dystrophic phenotype 5, 35, and importantly, are applicable to all DMD patients. Chronic AMPK activation was able to elicit the slow, oxidative myofiber program coincident with the amelioration of the dystrophic pathology in mdx mice 35, 36, 37, 38. This was accompanied by a significant increase in the UAPC along the sarcolemma [5]. Muscles with a greater abundance of slow and oxidative characteristics are more protected against DMD [39]. The precise mechanism that creates resilience to the dystrophic pathology in this fiber type is unknown. Interestingly, skeletal muscle knockout of AMPK results in decreased extrasynaptic utrophin expression in slow, oxidative muscles [40]. Furthermore, AICAR administration to dystrophin–utrophin double knockout animals caused the slow, oxidative phenotype transition in the absence of any functional improvements [41]. These results strongly suggest that utrophin is an important component of the protection afforded to dystrophic skeletal muscle in response to chronic AMPK stimulation. AMPK additionally benefits DMD by inducing corrective autophagy signaling 42, 43 (Figure 1C and Box 1). The characteristic muscle wasting in DMD may be partly attributed to defective autophagic processes and the resultant aggregation of dysfunctional and misfolded proteins [42]. Furthermore, muscles in DMD patients and preclinical murine models of DMD are burdened by the accumulation of damaged and dysfunctional mitochondria [44] due to a dysregulation in cargo-specific autophagy known as mitophagy [45]. Correcting autophagy in DMD mitigates the dystrophic pathology 42, 46, and AMPK directly stimulates the master regulator of autophagy unc-51-like autophagy activating kinase 1 (ULK-1), thereby triggering the initiation of autophagic cascades [47]. In fact, chronic AICAR administration in mdx mice elicited significant elevations in autophagy markers without exacerbating muscle atrophy [46]. Thus, the capability of AMPK to induce proautophagic signaling promotes protection of the muscle by inducing a more efficient recycling of damaged and defective proteins brought on by the dystrophic pathology. AMPK loss-of-function and rescue studies have shown that AMPK in macrophages and satellite palovarotene (SCs) are necessary for regeneration in skeletal muscle 48, 49, 50. Gain-of-function experiments employing pharmacological AMPK stimulation support this assertion (Figure 1C). For instance, AICAR-induced AMPK activation during the myopathy elicited by mitochondrial disease significantly alleviated the pathology, primarily by promoting muscle regeneration [51]. Metformin (MET) treatment also protected muscle from cardiotoxin-induced injury by preventing Ca2+ influx, thereby attenuating prodeath signaling [52]. Collectively, the evidence supports the notion that by regulating multiple, complementary cellular processes, AMPK effectively alleviates the DMD pathology.
    SMA and the Therapeutic Potential of AMPK As the leading genetic cause of infant mortality, SMA is a health- and life-limiting NMD, which at about 1/10000 live births is also the second most prevalent autosomal recessive disease. SMA is caused by homozygous mutations in the survival of motor neuron (SMN) 1 gene (SMN1), leading patients to rely on the SMN2 gene to produce SMN protein 53, 54, 55. However, SMN2 contains a single-base difference between SMN1, which leads to alternative splicing and exclusion of exon 7 in about 80–90% of SMN2 transcripts, creating a truncated, nonfunctional, and rapidly degraded translation product known as SMNΔ7 (Box 2 and Figure 2A,B). Approximately 10–20% of the SMN2 mRNAs produced are full-length (FL) transcripts, which are synthesized into functional FL-SMN protein. Although SMA is classically characterized by the degeneration of αMNs leading to secondary complications within skeletal muscle such as wasting and weakness, more recent evidence clearly indicates that muscle is also an important locus of SMA etiology independent of αMN deterioration 53, 54. The most promising therapeutic strategy for SMA utilizes ASO technologies to upregulate FL-SMN production from SMN2. In fact, the ASO nusinersen was recently approved for use in pediatric and adult patients with SMA. However, limitations of the compound include its sole dependence on SMN-mediated corrective mechanisms, as well as its lack of distribution and effectiveness in peripheral tissues such as skeletal muscle. This latter point is important to consider, since recent studies have demonstrated that the periphery must be targeted to elicit maximum therapeutic benefits from current generation ASOs, including nusinersen [56]. Moreover, therapies that augment SMN levels might not benefit all patients, based on evidence from mouse models [57]. For these reasons, approaches based on SMN-dependent and SMN-independent mechanisms, active across multiple affected tissues, continue to be pursued.