Pharmacological AMPK activation induces transcriptional responses congruent to exercise in skeletal and cardiac muscle, adipose tissues and liver

Abstract

Physical activity promotes metabolic and cardiovascular health benefits that derive in part from the transcriptional responses to exercise that occur within skeletal muscle and other organs. There is interest in discovering a pharmacologic exercise mimetic that could imbue wellness and alleviate disease burden. However, the molecular physiology by which exercise signals the transcriptional response is highly complex, making it challenging to identify a single target for pharmacological mimicry. The current studies evaluated the transcriptome responses in skeletal muscle, heart, liver, and white and brown adipose to novel small molecule activators of AMPK (pan-activators for all AMPK isoforms) compared to that of exercise. A striking level of congruence between exercise and pharmacological AMPK activation was observed across the induced transcriptome of these five tissues. However, differences in acute metabolic response between exercise and pharmacologic AMPK activation were observed, notably for acute glycogen balances and related to the energy expenditure induced by exercise but not pharmacologic AMPK activation. Nevertheless, intervention with repeated daily administration of short-acting activation of AMPK was found to mitigate hyperglycemia and hyperinsulinemia in four rodent models of metabolic disease and without the cardiac glycogen accretion noted with sustained pharmacologic AMPK activation. These findings affirm that activation of AMPK is a key node governing exercise mediated transcription and is an attractive target as an exercise mimetic.

CARM1 Regulates AMPK Signaling in Skeletal Muscle

“…MK-8722 is a potent pharmacological activator of all 12 AMPK isoforms ( Myers et al., 2017 ; Muise et al., 2019 ). The compound directly binds to the allosteric drug and metabolite site located at the interface between the α-subunit kinase domain and the carbohydrate-binding module in the β-subunit, which is thought to protect Thr172 from dephosphorylation ( Steinberg and Carling, 2019 ).…”

Downregulation of the Glo1 Gene Is Associated with Reduced Adiposity and Ectopic Fat Accumulation in Spontaneously Hypertensive Rats

“…Hypothetically, MG can stimulate AMPK activation via direct or indirect pathways. MG can increase the AMP-to-ATP ratio, a stimulus for AMPK, by decreasing the mitochondrial membrane potential and intracellular ATP levels [18][19][20]. AMPK can also be activated by oxidative stress via the classical AMP-mediated pathway [21].…”

PAN-AMPK Activation Improves Renal Function in a Rat Model of Progressive Diabetic Nephropathy

“…However, because these effects on heart weight are consistent with our previous experience in diabetic mouse models in which there was limited weight loss, it is reasonable to infer there may be a direct effect on heart (Myers et al, 2017; Muise et al, 2019). Interestingly, however, our laboratory recently reported that short-acting AMPK activators achieve transcriptional responses that are highly similar to those generated by longacting AMPK activators (like MK-8722) in skeletal and cardiac muscle, liver, and adipose tissue, though renal transcriptional responses were not assessed (Muise et al, 2019). Importantly, in those studies, the daily administration Fig.…”