Impact of the AMPK gamma2 R302Q Mutation on Human Skeletal Muscle Metabolism

AMP-activated protein kinase, AMPK, is a heterotrimeric protein complex comprised of an alpha catalytic, and of beta and gamma regulatory subunits. It is widely conserved across most organisms and is commonly referred to as the master regulator of cellular metabolism. By responding to increases in the AMP:ATP ratio, AMPK promotes ATP producing catabolic pathways, while simultaneously inhibiting ATP consuming anabolic pathways. Naturally occurring mutations in AMPK exist in various organisms and these can have a severe impact on fuel storage and metabolism. One such mutation in humans is the R302Q mutation in the gamma2 subunit; the outcome is accelerated glycogen production and impaired electrical conductance within the heart, resulting in Wolff-Parkinson White (WPW) syndrome. The impact of this rare mutation on AMPK activity is not well understood. By examining skeletal muscle samples from affected patients from the Ottawa region, we strove to determine the impact of the R302Q mutation on AMPK activity, and skeletal muscle metabolism. Skeletal muscle biopsies were utilized for histological analyses and cell culture determinations of fuel storage and AMPK activity. Trends for decreased triglyceride storage and increased glycogen storage, as well as impaired basal and AMP-stimulated AMPK activity were observed in the affected patient populations. Corollary work done in an adenoviral infected C2C12 muscle cell line expressing human gamma2 WT or the R302Q variant yielded no difference between groups in fuel storage or protein phosphorylation due to limitations (infection efficiency) of this model