Effects of decreased lactate accumulation after dichloroacetate administration on exercise training-induced mitochondrial adaptations in mouse skeletal muscle

Abstract

Recent studies suggested that lactate accumulation can be a signal for mitochondrial biogenesis in skeletal muscle. We investigated whether reductions in lactate concentrations in response to dichloroacetate (DCA), an activator of pyruvate dehydrogenase, attenuate mitochondrial adaptations after exercise training in mice. We first confirmed that DCA administration (200 mg/kg BW by i.p. injection) 10 min before exercise decreased muscle and blood lactate concentrations after high-intensity interval exercise (10 bouts of 1 min treadmill running at 40 m/min with a 1 min rest). At the same time, exercise-induced signal cascades did not change by pre-exercise DCA administration. These results suggested that DCA administration affected only lactate concentrations after exercise. We next examined the effects of acute DCA administration on mRNA expressions involved with mitochondrial biogenesis after same high-intensity interval exercise and the effects of chronic DCA administration on mitochondrial adaptations after high-intensity interval training (increasing intensity from 38 to 43 m/min by the end of training period). Acute DCA administration did not change most of the exercise-induced mRNA upregulation. These data suggest that lactate reductions by DCA administration did not affect transcriptional activation after high-intensity interval exercise. However, chronic DCA administration attenuated, in part, mitochondrial adaptations such as training-induced increasing rates of citrate synthase (P = 0.06), β-hydroxyacyl CoA dehydrogenase activity (P < 0.05), cytochrome c oxidase IV (P < 0.05) and a fatty acid transporter, fatty acid translocase/CD36 (P < 0.05), proteins after exercise training. These results suggest that lactate accumulation during high-intensity interval exercise may be associated with mitochondrial adaptations after chronic exercise training.

Lactate administration activates the ERK1/2, mTORC1, and AMPK pathways differentially according to skeletal muscle type in mouse

“…Interestingly, Hoshino and colleagues (Hoshino et al. ) showed that prior administration of dichloroacetate decreased lactate accumulation in blood and muscle during exercise which tended to decrease phosphorylation of AMPK Thr172 , suggesting a role of lactate in AMPK activation in skeletal muscle. In this study, we found that lactate stimulation trended toward increasing the phosphorylation of AMPK Thr172 and significantly increased ACC Ser79 in Sol, without changes in Quad and EDL.…”

Lactate as a Signaling Molecule That Regulates Exercise-Induced Adaptations

“…Additionally, decreased lactate accumulation in response to chronic dichloroacetate (an activator of PDH) administration reduced the mitochondrial adaptations to high-intensity interval training in mice. Citrate synthetase (CS), beta-HAD, and COXIV as well as the fatty acid transporter FAT/CD36 expression and protein content are increased with high-intensity interval training; however, when dichloroacetate was administrated (and lactate reduced), these adaptations were attenuated [50]. Moreover, PDK isoform 4 (which inhibits the conversion of lactate to pyruvate) and UCP3 (uncoupling protein 3, which improves mitochondrial oxidative capacity) were also increased with lactate administration in mouse muscle fibers—both proteins that are also upregulated by PGC-1 alpha [51].…”

Lactate administration increases mRNA expression of PGC-1α and UCP3 in mouse skeletal muscle

“…The increase in PGC-1α mRNA levels during recovery from acute exercise is known to be dependent on exercise intensity (Egan et al 2010). However, our group recently reported that reduced lactate accumulation following administration of dichloroacetate, an activator of pyruvate dehydrogenase, attenuated the high-intensity interval training-induced mitochondrial adaptations in mouse skeletal muscles (Hoshino et al 2015). To address the hypothesis that lactate plays an important role in exercise-induced metabolic adaptations, possibly via activation of PGC-1α in skeletal muscles, we administered lactate at upper physiological levels (~20 mM) that can be reached during an "all-out" maximal exercise (Goodwin et al 2007;Abe et al 2015).…”