br Concluding Remarks and Future

Concluding Remarks and Future Perspectives The collective evidence from studies detailing the functions of AMPK in the neuromuscular system, combined with those in DMD, SMA, and DM1 surveyed in the present review, strongly suggests that AMPK is a central mediator of neuromuscular determination, maintenance, and plasticity in health and disease. To be clear, however, numerous questions remain regarding AMPK in αMNs, at the NMJ, and in skeletal muscle that will require the concerted efforts of many to effectively address (see Outstanding Questions). The utilization of models that specifically upregulate or inhibit AMPK activity, as well as those that overexpress or knockout the kinase in the NMD context, for example in mice with SMA, will help address these critical knowledge gaps. The combination of complementary lifestyle and drug treatment strategies to target AMPK, for instance the prescription of exercise with orally bioactive small molecule agonists, represents a practical and effective possibility for future NMD therapies, such as those implemented in current AMPK-focused approaches for the treatment of metabolic diseases. Thus, further investigating the role of AMPK in αMNs, at the NMJ, and in myofibers will provide important insight into the mechanisms that regulate remodeling of the neuromuscular system, which will inform future avenues of AMPK-based therapeutics for NMDs.
Acknowledgments Work in the authors’ laboratory is funded by the Canadian Institutes of Health Research (CIHR), the Natural Sciences and Engineering Research Council of Canada, and the Canada Research Chairs program. V.L. is the Canada Research Chair (Tier 2) in Neuromuscular Plasticity in Health and Disease. A.M. is the recipient of a CIHR Canada Graduate Scholarship. We are grateful to all members of the Integrative Neuromuscular Biology Laboratory and Exercise Metabolism Research Group at McMaster University for insightful discussions and stimulating culture.
A long, long time ago, in a laboratory not so far away, Hetherington and Ranson first demonstrated that several different Nutlin 3 centers modulated energy balance , . Specifically, they showed that lesions in certain hypothalamic nuclei promoted differential responses in rodents. These findings gave rise to what became known as the ‘dual-center hypothesis’. In this model, food intake was controlled by two hypothalamic sites: the lateral hypothalamic ‘feeding centers’ and ventromedial hypothalamic ‘satiety centers’. Since then, our knowledge concerning the hypothalamic regulation of energy homeostasis has increased; however, the main concept is the same: anatomically defined hypothalamic nuclei form interconnected neuronal circuits, which respond to changes in energy status by altering the expression/function of specific neuropeptides and neurotransmitters. Ultimately, this results in changes in food intake, energy expenditure (EE), metabolism, and substrate utilization by peripheral organs . The modulation of metabolism is, essentially, a matter of energy fluxes. In fact, the marked fluctuations in nutrient availability and energy demand a very precise fine-tuning between anabolic and catabolic processes at the cellular and whole-body level. Therefore, living organisms have developed nutrient and energy sensors to adjust energy signaling pathways. One of these molecules is AMP-activated protein kinase (AMPK), which is technically the unique and genuine energy sensor. By detecting changes in the ratio of adenine nucleotides (AMP:ATP and ADP:ATP), AMPK is activated by stresses that diminish cellular energy status. AMPK activation promotes a global metabolic counter-regulatory response that turns off ATP-consuming processes, whilst turning on catabolic processes. The overall effect of AMPK activation is to produce ATP and restore the AMP:ATP and ADP:ATP ratios , . The role of AMPK as a master cellular energy gauge, first proposed in 1997 by David Carling and Grahame Hardie, has been extensively investigated during the following two decades. In terms of whole-body metabolic regulation, the next breakthrough came in 2004, when the groups of David Carling, Caroline Small, and Barbara Kahn demonstrated in two parallel seminal papers that hypothalamic AMPK played a major role in the modulation of whole-body energy homeostasis. They showed that (i) AMPK is highly expressed in several hypothalamic sites, such as the arcuate (ARC), dorsomedial, paraventricular (PVH), and ventromedial (VMH) nuclei, as well as in the lateral hypothalamic area; (ii) activation of hypothalamic AMPK leads to increased feeding and body weight gain, while its inhibition leads to hypophagia and weight loss; and (iii) hormones controlling feeding, such as leptin, insulin, and ghrelin, along with glucose, modulate hypothalamic AMPK , . Further work demonstrated that hypothalamic actions of AMPK were dichotomic, and while the effect of AMPK on feeding occurred mainly in the ARC , , AMPK in the neighboring VMH played a more integrative role by regulating (besides feeding) brown adipose tissue thermogenesis (and therefore EE), the browning of white adipose tissue, and peripheral glucose and lipid metabolism , , ().