LKB1 and AMPK and the regulation of skeletal muscle metabolism

Abstract

Purpose of review: To address the role of LKB1 and AMP-activated protein kinase (AMPK) in glucose transport, fatty acid oxidation, and metabolic adaptations in skeletal muscle.

Recent findings: Contraction-mediated skeletal muscle glucose transport is decreased in muscle-specific LKB1 knockout mice, but not in whole body AMPKalpha2 knockout mice or AMPKalpha2 inactive transgenic mice. Chronic activation of AMPK by 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) and beta-guanadinopropionic acid enhances mitochondrial function in skeletal muscle, but AICAR or exercise-induced increases in mitochondrial markers are preserved in skeletal muscles from whole body AMPKalpha2 or muscle-specific LKB1 knockout mice. Pharmacological activation of AMPK increases glucose transport and fatty acid oxidation in skeletal muscle. Therefore, chronic activation of AMPK may be beneficial in the treatment of obesity and type 2 diabetes.

Summary: LKB1 and AMPK play important roles in regulating metabolism in resting and contracting skeletal muscle.

Figure 1. Activation of AMPK and metabolic consequences

AMPK activation increases catabolic reactions, which generate ATP and inhibits anabolic reactions, which consume ATP.

Figure 2. Schematic illustration of the pathways which are thought to regulate contraction-stimulated glucose transport in skeletal muscle

Contraction increases the [AMP]/[ATP] ratio, activates AMPK, and subsequently induces glucose transport. Studies using muscle-specifc LKB1 knockout, whole body AMPKα2 knockout, and AMPKα2 inactive transgenic mice suggest that there may be multiple pathways involved in contraction-stimulated glucose transport. Solid arrows illustrate established relationships, and dashed arrows indicate putative interactions. CaMKK, Ca²⁺/calmodulin kinase kinase.