Background: The growing interest in how exercise and carbohydrate (CHO) restriction may modify molecular responses that promote endurance adaptations has led to many interesting controversies. Objective: We conducted a systematic review and a meta-analysis regarding the effect of low-carbohydrate availability (LOW) pre-, during, or post-exercise, on the mRNA content of commonly measured genes involved in mitochondrial biogenesis (PGC-1a, TFAM mRNA) and metabolism (PDK4, UCP3 and GLUT4 mRNA), and on muscle glycogen levels, compared with a high-CHO (CON) condition. Methods: MEDLINE, Scopus, and Web of Science databases were searched following the PRISMA 2020 guidelines (with an end date of November 2023). In total, 19 randomized-controlled studies were considered for inclusion. We evaluated the methodological quality of all studies using the Cochrane Risk of Bias tool for randomized clinical studies. A meta-analysis was performed using a random effects model to calculate the standardized mean difference (SMD), estimated by Hedges` g, and 95% confidence intervals (CIs). Results: The LOW condition was associated with an increased mRNA content of several genes during the early recovery period post-exercise, such as PDK4 (SMD 1.61; 95% CI 0.80-2.42), GLUT4 (SMD 1.38; 95% CI 0.46-2.30), and UCP3 (SMD 2.05; 95% CI 0.40-3.69). However, overall, there was no significant effect on the mRNA content of PGC-1a or TFAM. Finally, CHO restriction and exercise significantly reduced muscle glycogen levels (SMD 3.69; 95% CI 2.82-5.09). A meta-analysis of subgroups from studies with a difference in muscle glycogen concentration of > 200 mmol kg dw-1 between the LOW and CON conditions showed an increase in exercise-induced PGC-1a mRNA (SMD 2.08; 95% CI 0.64-3.52; p = 0.005; I2 = 75%) and a greater effect in PDK4 and GLUT4 mRNA. Conclusion: The meta-analysis results show that CHO restriction was associated with an increase in the exercise-induced mRNA content of PDK4, UCP3, and GLUT4, but not the exercise-induced mRNA content of PGC-1? and TFAM. However, when there were substantial differences in glycogen depletion between CON and LOW CHO conditions (> 200 mmol kg dw-1), there was a greater effect of CHO restriction on the exercise-induced mRNA content of metabolic genes, and an increase in exercise-induced PGC-1a mRNA.
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