Fuel economy in food-deprived skeletal muscle: signaling pathways and regulatory mechanisms

Energy deprivation poses a tremendous challenge to skeletal muscle. Glucose (ATP) depletion causes muscle fibers to undergo rapid adaptive changes toward the use of fatty acids (instead of glucose) as fuel. Physiological situations involving energy deprivation in skeletal muscle include exercise and fasting. A vast body of evidence is available on the signaling pathways that lead to structural/metabolic changes in muscle during exercise and endurance training. In contrast, only recently has a systematic, overall picture been obtained of the signaling processes (and their kinetics and sequential order) that lead to adaptations of the muscle to the fasting state. It has become clear that the reaction of the organism to food restraint or deprivation involves a rapid signaling process causing skeletal muscles, which generally use glucose as their predominant fuel, to switch to the use of fat as fuel. Efficient sensing of glucose depletion in skeletal muscle guarantees maintained activity in those tissues that rely entirely on glucose (such as the brain). To metabolize fatty acids, skeletal muscle needs to activate complex transcription, translation, and phosphorylation pathways. Only recently has it become clear that these pathways are interrelated and tightly regulated in a rapid, transient manner. Food deprivation may trigger these responses with a timing/intensity that differs among animal species and that may depend on their individual ability to induce structural/metabolic changes that serve to safeguard whole-body energy homeostasis in the longer term. The increased cellular AMP/ATP ratio induced by food deprivation, which results in activation of AMP-activated protein kinase (AMPK), initiates a rapid signaling process, resulting in the recruitment of factors mediating the structural/metabolic shift in skeletal muscle toward this change in fuel usage. These factors include peroxisome proliferator-activated receptor (PPAR)gamma coactivator-1alpha (PGC-1alpha), PPARdelta, and their target genes, which are involved in the formation of oxidative muscle fibers, mitochondrial biogenesis, oxidative phosphorylation, and fatty acid oxidation. Fatty acids, besides being the fuel for mitochondrial oxidation, have been identified as important signaling molecules regulating the transcription and/or activity of the genes or gene products involved in fatty acid metabolism during food deprivation. It is thus becoming increasingly clear that fatty acids determine the economy of their own usage. We discuss the order of events from the onset of food deprivation and their importance.

Energy deprivation poses a tremendouschallenge to skeletal muscle. Glucose (ATP) depletioncauses muscle fibers to undergo rapid adaptive changestoward the use of fatty acids (instead of glucose) asfuel. Physiological situations involving energy deprivationin skeletal muscle include exercise and fasting. Avast body of evidence is available on the signalingpathways that lead to structural/metabolic changes inmuscle during exercise and endurance training. Incontrast, only recently has a systematic, overall picturebeen obtained of the signaling processes (and theirkinetics and sequential order) that lead to adaptationsof the muscle to the fasting state. It has become clearthat the reaction of the organism to food restraint ordeprivation involves a rapid signaling process causingskeletal muscles, which generally use glucose as theirpredominant fuel, to switch to the use of fat as fuel.Efficient sensing of glucose depletion in skeletal muscleguarantees maintained activity in those tissues thatrely entirely on glucose (such as the brain). To metabolizefatty acids, skeletal muscle needs to activatecomplex transcription, translation, and phosphorylationpathways. Only recently has it become clear thatthese pathways are interrelated and tightly regulated ina rapid, transient manner. Food deprivation may triggerthese responses with a timing/intensity that differsamong animal species and that may depend on theirindividual ability to induce structural/metabolicchanges that serve to safeguard whole-body energyhomeostasis in the longer term. The increased cellularAMP/ATP ratio induced by food deprivation, whichresults in activation of AMP-activated protein kinase(AMPK), initiates a rapid signaling process, resulting inthe recruitment of factors mediating the structural/metabolic shift in skeletal muscle toward this change infuel usage. These factors include peroxisome proliferator-activated receptor (PPAR) coactivator-1 (PGC-1), PPAR, and their target genes, which are involvedin the formation of oxidative muscle fibers, mitochondrialbiogenesis, oxidative phosphorylation, and fattyacid oxidation. Fatty acids, besides being the fuel formitochondrial oxidation, have been identified as importantsignaling molecules regulating the transcriptionand/or activity of the genes or gene products involvedin fatty acid metabolism during food deprivation. It isthus becoming increasingly clear that fatty acids determinethe economy of their own usage. We discuss theorder of events from the onset of food deprivation andtheir importance.