(771.9) AICAR rejuvenates treadmill running performance and skeletal muscle gene expression in sarcopenic mice

Poster Board Number: E615

Jouber Calixto (Brigham Young University), Connor Johnson (Brigham Young University), Andrew Smith (Brigham Young University), Kole Brodowski (Brigham Young University), Shalene Wilcox (Brigham Young University), Jonathon Hill (Brigham Young University), David Thomson (Brigham Young University, Xenter Therapeutics)

Physical exercise is widely regarded as the most effective strategy for preserving muscle and systemic function in old age. The exercise-induced signals that mediate exercise’s effects are varied and almost certainly not fully cataloged. Nonetheless, adenosine monophosphate (AMP) is clearly important in exercise’s beneficial adaptations. AMP is an intracellular indicator of ATP utilization during exercise and other forms of energetic stress. Its accumulation leads to the activation of AMP-activated protein kinase (AMPK) and the regulation of other metabolic enzymes, including phosphofructokinase-1 and glycogen phosphorylase. The prodrug AICAR mimics AMP accumulation by increasing the concentration of the AMP analog, ZMP. The primary purpose of the present study was to determine the effect of chronic (31 days) AICAR treatment on muscle gene expression and function in old (O; 24 mo.) mice. AICAR attenuated muscle atrophy in O mice, and completely eliminated an age-associated decline in treadmill running performance. It also tended to increase in-vitro muscle force production in O mice. RNA sequencing identified 692 gene ontologies that were rejuvenated by AICAR treatment (where AICAR reversed gene expression changes in O vs. young [5 mo. old] mice). Among these AICAR regulated ontologies, those related to mitochondria, extracellular matrix/collagen, catabolism, and stress response were highly represented. Our results demonstrate that the AMP-mimetic AICAR can mediate an exercise-like reversal of age-related changes in muscle gene expression and function. Its effects may also be relevant in other conditions in which muscle function is compromised.