Molecular Regulation of Fatty Acid Oxidation in Skeletal Muscle during Aerobic Exercise

The regulation of fatty acid (FA) oxidation during exercise is subject to multisite control allowing flexible regulation of metabolism. FA uptake is facilitated via cluster of differentiation 36/SR-B2 (CD36), which translocates to the sarcolemma at the onset of muscle contractions, thereby increasing intracellular FA availability. Carnitine availability plays an essential role in the regulation of FA oxidation. Sequestering of acetyl-CoA to carnitine by carnitine acetyltransferase (CAT) alters the free carnitine content in muscle thereby influencing the carnitine palmitoyltransferase 1 (CPT1) reaction and in turn mitochondrial FA import and oxidation. This scenario may explain the lower FA oxidation at higher exercise intensities where a high glycolytic rate leads to acetyl-CoA excess, whereas the potential for FA import into the tricarboxylic acid cycle is enhanced when the glycolytic rate is low, as during prolonged low-intensity exercise. This review summarizes how fatty acid (FA) oxidation is regulated in skeletal muscle during exercise. From the available evidence it seems that acetyl-CoA availability in the mitochondrial matrix adjusts FA oxidation to exercise intensity and duration. This is executed at the step of mitochondrial fatty acyl import, as the extent of acetyl group sequestration by carnitine determines the availability of carnitine for the carnitine palmitoyltransferase 1 (CPT1) reaction. The rate of glycolysis seems therefore to be central to the amount of β-oxidation-derived acetyl-CoA that is oxidized in the tricarboxylic acid (TCA) cycle. FA oxidation during exercise is also determined by FA availability to mitochondria, dependent on trans-sarcolemmal FA uptake via cluster of differentiation 36/SR-B2 (CD36) and FAs mobilized from myocellular lipid droplets. This review summarizes how fatty acid (FA) oxidation is regulated in skeletal muscle during exercise. From the available evidence it seems that acetyl-CoA availability in the mitochondrial matrix adjusts FA oxidation to exercise intensity and duration. This is executed at the step of mitochondrial fatty acyl import, as the extent of acetyl group sequestration by carnitine determines the availability of carnitine for the carnitine palmitoyltransferase 1 (CPT1) reaction. The rate of glycolysis seems therefore to be central to the amount of β-oxidation-derived acetyl-CoA that is oxidized in the tricarboxylic acid (TCA) cycle. FA oxidation during exercise is also determined by FA availability to mitochondria, dependent on trans-sarcolemmal FA uptake via cluster of differentiation 36/SR-B2 (CD36) and FAs mobilized from myocellular lipid droplets. it could be argued whether use of the term ‘long-chain FAs’ would be more appropriate, but as the main in vitro evidence on intramyocellular FA metabolism has not extensively investigated the role of FA type, the general term ‘FA’ seems more appropriate, without referral to chain length or FA saturation status. It should be noted that the regulation of plasma membrane FA transport has mainly been investigated by the use of long-chain FA tracers in the form of palmitate or oleate and it is also well documented that long-chain, but not medium- or short-chain, FAs require CPT1 to enter the mitochondrial matrix. membrane vesicles with a diameter of approximately 10–15 μm that can be derived from muscle tissue by collagenase treatment. The vesicles are formed by budding of the plasma membrane and are oriented right-side out (important for transport studies) and with minimal contamination with other membrane components and cellular organelles. in this model exercise is allocated to one muscle group, the knee extensors (quadriceps femoris). Usually, one leg is subjected to dynamic knee extensions while the other leg serves as internal rested control. In this model the autonomic neuroendocrine response is markedly lower than that observed during whole-body exercise. Oxygen and substrate delivery are also not restricted and muscle metabolism can be quantified directly. refers to the hydrolysis of TG to FAs and glycerol. The liberation of three FA moieties from intracellular TG stores requires three consecutive steps that involve three different lipases: ATGL catalyzes the conversion of TG to diacylglycerol and HSL generates monoacylglycerol, which finally is hydrolyzed by monoacylglycerol lipase (MGL). an estimate of whole-body substrate metabolism measured by indirect calorimetry. RER is given as the ratio between exhaled CO2 and O2 consumption during respiration. A RER of 0.7 indicates that FAs are the sole substrate source, while 1.0 is indicative of carbohydrate being the sole substrate. RER values in the range between 0.7 and 1 thus indicate mixed FA and carbohydrate utilization. The RER estimate does not take into account amino acid oxidation, which comprises only a minor fraction (4–8%) both at rest and during exercise. At rest RER is about 0.8–0.85 when a mixed diet is consumed. During low- to moderate-intensity exercise, RER equals around 0.85, increasing gradually beyond 50–65% of VO2max. During high-intensity exercise, evaluations of substrate oxidation by indirect calorimetry should be interpreted with caution, due to lactate production when the contribution of anaerobic energy replenishment increases. As a result, ventilatory CO2 release exceeds metabolic CO2 production. Therefore, measurement of the true metabolic RER (and hence FA oxidation) may prove more difficult at high exercise intensities.