Effects of Lactate Administration on Mitochondrial Respiratory Function in Mouse Skeletal Muscle

Abstract

Recent evidence has shown that mitochondrial respiratory function contributes to exercise performance and metabolic health. Given that lactate is considered a potential signaling molecule that induces mitochondrial adaptations, we tested the hypothesis that lactate would change mitochondrial respiratory function in skeletal muscle. Male ICR mice (8 weeks old) received intraperitoneal injection of PBS or sodium lactate (1 g/kg BW) 5 days a week for 4 weeks. Mitochondria were isolated from freshly excised gastrocnemius muscle using differential centrifugation and were used for all analyses. Lactate administration significantly enhanced pyruvate + malate- and glutamate + malate-induced (complex I-driven) state 3 (maximal/ATP synthesis-coupled) respiration, but not state 2 (basal/proton conductance) respiration. In contrast, lactate administration significantly decreased succinate + rotenone-induced (complex II-driven) state 3 and 2 respiration. No significant differences were observed in malate + octanoyl-l-carnitine-induced state 3 or 2 respiration. The enzymatic activity of complex I was tended to increase and those of complexes I + III and IV were significantly increased after lactate administration. No differences were observed in the activities of complexes II or II + III. Moreover, lactate administration increased the protein content of NDUFS4, a subunit of complex I, but not those of the other components. The present findings suggest that lactate alters mitochondrial respiratory function in skeletal muscle.

3-phenyllactic acid promotes healthspan through SKN-1/ATFS-1-mediated mitochondrial activation and stress resilience

“…Interestingly, PLA specifically interacted with MRCC II (Figure 3K) and MRCC V (Figure 3L), while no interactions were observed with the remaining MRCCs (Figures S4A-S4C). This interaction was notable for its specificity and surprising similarity to the effects of lactate administration on MRCC in mouse skeletal muscle 32 . Furthermore, in accordance with previous studies on bioenergetic health assessment in C. elegans 33,34 , we observed a dose-dependent increase in oxygen consumption rate under PLA treatment.…”

“…Interestingly, PLA specifically interacted with MRCC II (Figure 3K) and MRCC V (Figure 3L), while no interactions were observed with the remaining MRCCs (Figures S4A-S4C). This interaction was notable for its specificity and surprising similarity to the effects of lactate administration on MRCC in mouse skeletal muscle 32 .…”

Deciphering the Therapeutic Role of Lactate in Combating Disuse-Induced Muscle Atrophy: An NMR-Based Metabolomic Study in Mice

“…The LAC mice received daily intraperitoneal injections of sodium lactate (#71718, Sigma-Aldrich, Shanghai, China) (1 g/kg/day) concurrent with the establishment of the DMA model. The dosage of lactate was selected based on its proven therapeutic efficacy in promoting cell proliferation, as has been established in previous studies and supported by literature indicating beneficial outcomes [15,18].…”

“…Lactate not only serves as an essential energy source for the liver and other tissues but also significantly contributes to the acid-base homeostasis of the body and profoundly affects exercise performance [13,14]. Moreover, lactate is increasingly being recognized as a signaling molecule that can initiate mitochondrial adaptations, impacting the respiratory functions of mitochondria in the skeletal muscles of mice [15]. Recent studies have also broadened our comprehension of the biological relevance of lactate, underscoring its role in regulating diverse signaling pathways [16,17].…”

Monocarboxylate transporter 4 deficiency enhances high‐intensity interval training‐induced metabolic adaptations in skeletal muscle

“…Researchers have studied the effects of increased lactate concentrations in the extracellular fluid or blood on the recipient cells and tissues. For instance, exogenous lactate administration has been shown to increase the content and function of mitochondria in skeletal muscle, promote beige adipogenesis and improve neuronal function (Carrière et al., 2014; Kitaoka et al., 2016; Magistretti & Allaman, 2018; Takahashi et al., 2020; Takahashi et al., 2022). Moreover, lactate functions as an intracellular signalling molecule, potentially modulating biological processes such as mitochondrial oxidative substrate selection, NAD + /NADH and reactive oxygen species (ROS) production and histone modifications (Brooks, 2020; Hashimoto et al., 2007; Philp et al., 2005; Zhang et al., 2019).…”