Roles of lactate in lactate oxidation complex, mitochondrial biogenesis and cell signaling in cultured L6 skeletal muscle cells

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Functional adaptations of muscle cells to exercise involve alterations in cell structure (1, 2), mitochondrial density and respiratory capacity (3-5), solute transport (6), and energy substrate partitioning (7). We are interested in defining the role of lactate as a metabolic signal that affects gene transcription. During contractions, muscle [lactate] can rise 1-2 orders of magnitude, and it has been postulated that lactate may serve as a pseudo-hormone because of its influence on cellular redox state by affecting the NAD^+/NADH ratio (6). However molecular mechanisms that cause these metabolic effects of lactate were uncharacterized. We hypothesized that lactate anion (La) is a signaling molecule whose actions affect the transcription of specific genes. Therefore, we screened genome-wide responses of L6 cells to elevated (10 and 20 mM) concentrations of sodium lactate in buffered, high-glucose containing media. Here we report on our efforts to describe the possible contribution of lactate to the transcription of genes known to be involved in the muscular adaptations to exercise stress (8). Analysis of 〜15,000 L6 genes revealed that La up-regulated 673 genes related to metabolism, mitochondrial biogenesis, transcriptional activation, signal transduction, solute transport, oxidative stress, apoptosis and cell growth; many of the genes are known to be responsive to reactive oxygen species (ROS) and Ca ^<2+>. Analysis of ROS in the cells showed that lactate augmented ROS production. Induction of selected genes and the encoded proteins was confirmed by independent methods (PCR and EMSA). Specifically, lactate increased transporter (MCT1) mRNA and protein expression within 1hr, as well as the increased expression of its chaperon protein CD147. Subsequently, La exposure increased cytochrome c oxidase (COX) mRNA and protein expression at 6hr. The increases in COX coincided with increases in peroxisome proliferator activated-receptor γ coactivator-1α (PGC1α) expression and the DNA binding activity of nuclear respiratory factor (NRF)-2 and cAMP-response element-binding protein (CREB), and our data suggest that La signaling cascade involves ROS production and converges on transcription factors that may affect expression of the mitochondrial lactate oxidation complex (MCT1, CD147, COX, and LDH) (9) and account for some of the metabolic effects of lactate. As well data provide insight into how lactate may serve as a signaling molecule (a "lactormone") eliciting transport protein expression, mitochondrial biogenesis and other adaptive responses to exercise stress by activating a vast transcriptional network.
2008-02-01

Roles of lactate in lactate oxidation complex, mitochondrial biogenesis and cell signaling in cultured L6 skeletal muscle cells

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