Interestingly metabolic dysfunction is also observed in

Interestingly, metabolic dysfunction is also observed in amyotrophic lateral sclerosis (ALS). Patients and mouse models of familial ALS exhibit higher levels of resting AZD 7762 mg expenditure and lower fat-free mass, indicating a hypermetabolic phenotype. Lim et al. (2012) found that reducing AMPK activity, either pharmacologically or genetically, protects against motor neuron degeneration and muscle pathology observed in genetic models of motor neuron disease. Similarly, Liu et al. (2015) found that cytoplasmic mislocalization of TAR DNA-binding protein-43 (TDP-4) inclusions (a hallmark of ALS) is associated with an increased activation of AMPK in motor neurons in patients with ALS.
Concluding remarks AMPK signaling is complex and one must avoid drawing simplistic conclusions based on conflicting reports. First of all, there are at least 12 types of possible AMPK trimeric complexes and little is known about which specific complex is preferentially formed within in a distinct cell, its exact subcellular localization or precise targeting set of substrates and whether there is the differential expression of AMPK isoforms in different pathological conditions (Dasgupta and Chhipa, 2016). When analyzing the seemingly discordant reports on the AMPK response, the experimental model (type of mouse strain and knockouts and type of cell cultures used), the stage of disease development and the specific cellular energy status of each neurodisease must be taken into consideration. In neuroinflammation disorders, the crucial challenge that warrants investigation is the possible benefits of AMPK agonists or antagonists in specific neurological contexts. Such efforts will certainly provide an opportunity to establish a rationale for the development of therapeutic strategies.
AMPK Structure and Function AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase that is stimulated by low cellular energy levels. The kinase is a heterotrimeric molecule, possessing catalytic α, scaffolding β, and regulatory γ subunits. Each AMPK subunit has multiple isoforms (i.e., α1, α2, β1, β2, γ1, γ2, and γ3) leading to a variety of possible αβγ heterotrimers that exhibit tissue-specific expression profiles. For example, human and rodent skeletal muscle heterotrimer composition includes primarily (i.e., 60–70%) the α2β2γ1, with some consideration given to muscle fiber type-specific AMPK composition 1, 2. The details of AMPK structure, function, and regulation are complex and beyond the scope of the current discussion; however, interested readers are invited to peruse recent, excellent reviews on these topics 1, 2, 3, 4. Via its phosphorylation of downstream targets, AMPK is a master regulator of cellular energy homeostasis. With regard to the neuromuscular system, the activation of AMPK has been shown to play a vital role in maintaining and remodeling skeletal muscle (see Glossary) phenotype 1, 2, 5, while emerging literature underscores the ability of the kinase to evoke plasticity of α-motoneurons (αMNs) and the neuromuscular junction (NMJ)6, 7, 8, 9. This review discusses studies that have capitalized on genetic, physiological, and pharmacological strategies to reveal the role of AMPK in regulating these processes, and presents evidence implicating AMPK as a therapeutic target in the most prevalent neuromuscular disorders (NMDs), including Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA), and myotonic dystrophy type 1 (DM1).
Regulation of Neuromuscular Biology by AMPK AMPK is a powerful regulator of skeletal muscle plasticity that can influence a wide range of structural and functional characteristics from fuel metabolism, to atrophy, regeneration, and fiber type 1, 2. For example, transgenic and pharmacological models of chronic AMPK activation clearly illustrate the importance of the kinase in driving characteristics indicative of a slower, more oxidative skeletal muscle phenotype. In general, animals lacking skeletal muscle AMPK are severely exercise intolerant and demonstrate a myopathy that includes reduced levels of mitochondria and a decrease in myofiber capillarization 10, 11. It is not surprising therefore that a constitutively active AMPK mutant demonstrates elevated mitochondrial biogenesis in skeletal muscle [12]. Pharmacological activation of AMPK by administration of 5′-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) promotes the slow, oxidative muscle phenotype, including an increase in peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) expression, a shift toward slower myosin heavy-chain composition, augmented mitochondrial biogenesis, as well as enhanced sarcolemmal integrity 13, 14. Recent studies employing novel, orally bioactive AMPK stimulators PF-739 and MK-8722 also demonstrate increased mitochondrial biogenesis due to activation of AMPK in skeletal muscle 15, 16. AMPK exerts its effects promoting slower, more oxidative muscle characteristics, in part, by stimulating the gene expression and activity of the transcriptional coactivator PGC-1α 17, 18, a powerful phenotype-bending molecule 19, 20. Mice deficient in AMPKα2 are exercise intolerant and display lower PGC-1α and mitochondrial contents [21], whereas AMPKγ1 mutants demonstrate elevated muscle PGC-1α and glycogen stores, and exercise capacity [21]. It is interesting to note that PGC-1α-null animals do not exhibit the same increased glucose transporter type 4 (GLUT4) and mitochondrial protein expression as wild-type (WT) animals after AICAR-induced AMPK activation [22]. These data provide additional, strong evidence that PGC-1α plays an important role in AMPK-mediated phenotype remodeling. Thus, AMPK activity effectively determines, maintains, and remodels skeletal muscle phenotype via mechanisms involving PGC-1α.