Exercise performance and peripheral vascular insufficiency improve with AMPK activation in high-fat diet-fed mice

Abstract

Intermittent claudication is a form of exercise intolerance characterized by muscle pain during walking in patients with peripheral artery disease (PAD). Endothelial cell and muscle dysfunction are thought to be important contributors to the etiology of this disease, but a lack of preclinical models that incorporate these elements and measure exercise performance as a primary end point has slowed progress in finding new treatment options for these patients. We sought to develop an animal model of peripheral vascular insufficiency in which microvascular dysfunction and exercise intolerance were defining features. We further set out to determine if pharmacological activation of 5'-AMP-activated protein kinase (AMPK) might counteract any of these functional deficits. Mice aged on a high-fat diet demonstrate many functional and molecular characteristics of PAD, including the sequential development of peripheral vascular insufficiency, increased muscle fatigability, and progressive exercise intolerance. These changes occur gradually and are associated with alterations in nitric oxide bioavailability. Treatment of animals with an AMPK activator, R118, increased voluntary wheel running activity, decreased muscle fatigability, and prevented the progressive decrease in treadmill exercise capacity. These functional performance benefits were accompanied by improved mitochondrial function, the normalization of perfusion in exercising muscle, increased nitric oxide bioavailability, and decreased circulating levels of the endogenous endothelial nitric oxide synthase inhibitor asymmetric dimethylarginine. These data suggest that aged, obese mice represent a novel model for studying exercise intolerance associated with peripheral vascular insufficiency, and pharmacological activation of AMPK may be a suitable treatment for intermittent claudication associated with PAD.

Pathogenesis of the Limb Manifestations and Exercise Limitations in Peripheral Artery Disease

“…53 In addition, in an animal model of chronic atherosclerosis that simulated some features of PAD, a pharmacological intervention that improved exercise-induced blood flow also improved the animals' functional status. 54 The impaired vasodilation in patients with PAD is likely a sequela of the obstruction, and improvement in physiological vasodilation with exercise offers a potential therapeutic target. Microcirculatory dysfunction and local skeletal muscle flow can also be assessed by novel noninvasive imaging techniques, including arterial spin-labeling MRI and contrast-enhanced ultrasound.…”

“…The indirect 5′ AMP-activated protein kinase activator R118 has improved exercise performance and vascular insufficiency in high-fat fed mice. 54 Although the overlapping metabolic functions of ERRα and ERRγ suggest potential benefit for patients with PAD, breast cancer association studies suggest that ERRα and ERRγ have differing effects on cancer progression, with high levels of ERRα associated with expression of ErbB2, increased risk of recurrence, and adverse clinical outcomes. 161,162 Thus, careful choices of pharmacological agents will need to be made if mitochondrial biogenesis in patients with PAD will be attempted through ERR modulation.…”

Adenosine Monophosphate-activated Protein Kinase (AMPK) Activators For the Prevention, Treatment and Potential Reversal of Pathological Pain

“…Therefore, based on the strong preclinical and emerging clinical evidence with this compound there are excellent reasons to pursue more potent and efficacious complex I inhibitors that activate AMPK via this mechanism. Recently, several molecules that fit this description have been described (125, 126) but to date none of them have been tested in preclinical models or even on DRG or TG neurons. One potential reason to favor complex I inhibitors versus other mechanisms of action for regulating AMPK is the emerging evidence for mitochondrial dysfunction in several forms of neuropathic pain (91, 127).…”

Enhancement of physical fitness by black ginger extract rich in polymethoxyflavones: a double-blind randomized crossover trial

“…We previously confirmed that PMFs, particularly 5,7-dimethoxyflavone in KPE, improved metabolism in muscle cells by activating AMPK [24]. AMPK is known to play a critical role in the regulation of energy homeostasis and is related to physical fitness, endurance, and fatigue [41][42][43][44][45][46][47][48]. For example, 5-aminoimidazole-4-carboxyamide ribonucleotide (AICAR), an AMPK agonist, was reported to increase running endurance by 44% and decrease body fat in mice following its oral administration for 4 weeks [48].…”