Lactate Metabolism and Mitochondrial Function in Skeletal Muscle

Lactate metabolism in skeletal muscle encompasses the production of lactate via glycolysis and its subsequent oxidation within mitochondria. Under conditions of increased energy demand or limited oxygen, glycolytic flux generates pyruvate that is reduced to lactate by lactate dehydrogenase, regenerating NAD+ for continued ATP production. Lactate is then exported via monocarboxylate transporters to the bloodstream, adjacent fibres or back into oxidative fibres where it enters mitochondria for oxidation. This process links anaerobic and aerobic metabolism, enabling metabolic flexibility during exercise and recovery.

Within mitochondria, lactate oxidation contributes carbon to the tricarboxylic acid cycle and supports ATP synthesis through oxidative phosphorylation. Beyond its role as a fuel, lactate acts as a signalling molecule, triggering mitochondrial biogenesis and adaptive responses that enhance oxidative capacity and endurance performance. Dysregulation of lactate handling is implicated in conditions ranging from metabolic inflexibility to muscle fatigue and insulin resistance, underscoring its global significance in both health and disease contexts.

Research from Nature Portfolio

Recent work on cultured myotubes has revealed that lactate functions beyond a metabolic intermediate, acting as a signal to induce intramuscular triglyceride storage and promote mitochondrial maintenance. The study demonstrated that lactate activates a G-protein-coupled lactate receptor, inhibits the cAMP–PKA pathway and enhances activities of key mitochondrial enzymes such as malonyl-CoA:ACP transferase and pyruvate dehydrogenase. It also upregulates expression of lactate transporters and the receptor itself, suggesting a positive feedback loop that coordinates lipid storage with mitochondrial biogenesis and function.

Lactate Metabolism and Mitochondrial Function in Skeletal Muscle publication trend

The graph below shows the total number of articles in lactate metabolism and mitochondrial function in skeletal muscle across all publications each year (not limited to Nature Index journals).

Technical terms

Lactate shuttle: Mechanism by which lactate is transported between cells or within cells to link glycolysis and oxidative metabolism.

Monocarboxylate transporter (MCT): Membrane proteins that facilitate transmembrane movement of lactate and other monocarboxylates.

Lactate dehydrogenase (LDH): Enzyme catalysing the reversible conversion of pyruvate to lactate with concomitant interconversion of NADH and NAD⁺.

Oxidative phosphorylation: Mitochondrial process generating ATP through electron transport and proton gradient across the inner membrane.

GPR81: A G-protein-coupled receptor activated by lactate involved in cellular signalling and metabolic regulation.

References

1. Lactate in contemporary biology: a phoenix risen. The Journal of Physiology (2021).
2. Induction of triglyceride accumulation and mitochondrial maintenance in muscle cells by lactate. Scientific Reports (2016).
3. Tracing the lactate shuttle to the mitochondrial reticulum. Experimental & Molecular Medicine (2022).
4. Chronic Lactate Exposure Decreases Mitochondrial Function by Inhibition of Fatty Acid Uptake and Cardiolipin Alterations in Neonatal Rat Cardiomyocytes. Frontiers in Nutrition (2022).