The role of GPR81-cAMP-PKA pathway in endurance training-induced intramuscular triglyceride accumulation and mitochondrial content changes in rats.

The athlete's paradox phenomenon involves the accumulation of intramuscular triglycerides (IMTG) in both insulin-resistant and insulin-sensitive endurance athletes. Nevertheless, a complete understanding of this phenomenon is yet to be achieved. Recent research indicates that lactate, a common byproduct of physical activity, may increase the accumulation of IMTG in skeletal muscle. This is achieved through the activation of G protein-coupled receptor 81 (GPR81) leads to the suppression of the cyclic adenosine monophosphate-protein kinase A (cAMP-PKA) pathway. The mechanism accountable for the increase in mitochondrial content in skeletal muscle triggered by lactate remains incomprehensible. Based on current research, our objective is to explore the role of the GPR81-inhibited cAMP-PKA pathway in the aggregation of IMTG and the increase in mitochondrial content as a result of prolonged exercise. The GPR81-cAMP-PKA-signaling pathway regulates the buildup of IMTG caused by extended periods of endurance training (ET). This is likely due to a decrease in proteins related to fat breakdown and an increase in proteins responsible for fat production. It is possible that the GPR81-cAMP-PKA pathway does not contribute to the long-term increase in mitochondrial biogenesis and content, which is induced by chronic ET. Additional investigation is required to explore the possible hindrance of the mitochondrial biogenesis and content process during physical activity by the GPR81-cAMP-PKA signal.

Role of GPR81 in regulating intramuscular triglyceride storage during aerobic exercise in rats.

Lactate, a metabolite of exercise, plays a crucial role in the body. In these studies, we aimed to investigate the role of G protein-coupled receptor 81 (GPR81), a specific receptor for lactate, in regulating lipid storage in the gastrocnemius muscle of rats. To achieve this, we measured the impact of sodium 3-hydroxybutyrate (3-OBA) concentration and time on the cAMP-PKA signaling pathway in the gastrocnemius muscles of rats. Our investigation involved determining the effects of administering 3-OBA at a concentration of 3 mmol L-1 just 15 min before exercise. As expected, exercise led to a notable increase in intramuscular lactate concentration in rats. However, injecting 3-OBA prior to exercise yielded intriguing results. It not only further augmented the cAMP-PKA signaling pathway but also boosted the expression of lipolysis-related proteins such as hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL). Simultaneously, it decreased the expression of fat-synthesizing proteins, including acetyl CoA carboxylase (ACC) and fatty acid synthase (FAS), while increasing the protein expression of cytochrome c oxidase subunit Ⅳ(COX Ⅳ) and the activity of citrate synthetase (CS). Unfortunately, there was no significant change observed in intramuscular triglyceride (IMTG) content. In summary, our findings shed light on the role of lactate in partially regulating intramuscular triglycerides during exercise.

The different effects of intramuscularly-injected lactate on white and brown adipose tissue in vivo.

BACKGROUND: Lactate is an important product of glycolysis metabolism during exercise and has long been recognized as an important metabolic signaling molecule involved in inhibiting lipolysis and promoting lipogenesis, which consequently leads to regulated adipose tissue metabolism. However, recent studies have shown that lactate promotes the browning of white adipose tissue (WAT), which induces heat production and energy expenditure and ultimately causes weight loss. These studies assessing the effects of lactate on lipid metabolism in adipose tissue have revealed conflicting data, making it an important area worthy of further research. METHODS: In this study, using intramuscular injection of lactate to the gastrocnemius, we identified the role of lactate treatment on lipid metabolism and mitochondrial biogenesis of white adipose tissue and brown adipose tissue (BAT). RESULTS: Our results showed that lactate treatment activated the cAMP/PKA signaling pathway and promoted the expression of lipolysis-related proteins (AMPK, HSL, ATGL) and mitochondrial biomarkers (PGC-1α, COXIV) of WAT, while BAT showed an opposite trend after lactate treatment. Further studies showed that lactate treatment significantly increased serum epinephrine and promoted ß3-AR protein expression in WAT and significantly decreased in BAT. CONCLUSION: Our study shows that lactate seems to regulate ß3-adrenergic receptors differently in WAT and BAT, thereby eliciting disparate responses in adipose tissue.