Regulation of Peripheral Molecular Clocks in Mammalian Tissues and In Vitro Skeletal Muscle Activation of AMP-Activated Protein Kinase via AICAR

Abstract

Most organisms possess a common molecular machinery that governs cellular and tissue circadian rhythmicity through a roughly 24-hour transcription-translation feedback loop. It is estimated that up to 15 percent of human genes are influenced by the core clock machinery. It is likely, however, that the metabolic networks affected by the molecular clock differ according to body tissue. Recent evidence suggests that peripheral molecular clocks are governed to a greater extent by energy availability than by light and dark cycles. AMP-activated protein kinase (AMPK) acts as a cellular fuel gauge within the cell and is activated in response to exercise and fasting. AMPK can also be pharmacologically activated by 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR). AMPK likely serves as an intermediary between metabolism and the molecular clock due to its activation of the rate-limiting enzyme in Nicotinamide adenine dinucleotide (NAD) biosynthesis, Nicotinamide phosphoribosyltransferase (NAMPT), and its role in PER and CRY degradation. The NAD-dependent histone deacetylase SIRT 1 inhibits the BMAL1-CLOCK complex in a NAMPT-dependent manner.The complex interplay between metabolism and peripheral clocks mediated by AMPK is beginning to be unraveled. AMPK’s tissue-specific influence on the molecular clock in skeletal muscles and other mammalian tissues requires further elucidation as it may provide insight into the etiology and treatment of metabolic disease. [excerpt