Lactate as a fuel for mitochondrial respiration

Lactate production in skeletal muscle has now been studied for nearly two centuries and still its production and functional role at rest and during muscle contraction is a subject of debate. Historically, skeletal muscle was seen mainly as the site of lactate production during contraction and lactate production associated with a lack of muscle oxygenation and fatigue. Later, it was recognized that skeletal muscle not only plays an important role in lactate production but also in lactate clearance and this in turn has led to a renewed interest in the metabolic fate of lactate in skeletal muscle and also in other tissues. Studies using lactate isotopes have shown that skeletal muscle extracts lactate from the circulation despite a substantial net lactate release, and that skeletal muscle has a large capacity for lactate oxidation; these processes being enhanced with exercise. Lactate dehydrogenase (LDH) controls the formation of lactate and may regulate the turnover of lactate in the muscle cell. Skeletal muscle contains five LDH isoforms (LDH1-5). Of the five LDH isoforms, the heart-specific LDH1, 2 is generally suggested to favour the reaction of lactate to pyruvate whereas the muscle-specific LDH4,5 isoform favours lactate formation. However, in this paper, it is argued that compartmentalization of the muscle cell and LDH association with cell structures may play a more predominant role in whether the LDH reaction proceeds towards lactate or pyruvate formation. The model for skeletal muscle lactate metabolism presented is in essence based on a synthesis of old and more recent studies on skeletal muscle lactate transport, uptake, release, oxidation, and the role of LDH at rest and during exercise.