Training-induced increase in mitochondrial biogenesis

University dissertation from Verona University, Italy

Abstract: Endurance training leads to an improved ability of muscle to utilize oxygen. This is related to an increased density and function of mitochondria. The biogenesis and adaptation of mitochondria is a complex process mediated by various signalling pathways and seems to be highly sensitive to the type of exercise and the local environment in the muscle. Changes in the muslce environment in terms of altered metabolism and substrate accumulation are affected by changes in acid/base balance in response to exercise. Recent studies have shown that changes in acid/base balance may affect the regulation of mitochondrial adaptation to acute exercise; however, how this responds to training and relates to performance adaptations in humans is unclear. Similarly, the effect of acid/base balance on molecular mechanisms underlying mitochondrial biogenesis is unclear. The objectives of this thesis were to examine the relationship between acid/base balance, mitochondrial biogenesis and adaptation and explore the mechanisms which regulate mitochondrial adaptation. To realize these aims a series of related investigations were undertaken. Initially, cultured L6 myotubes were used to assess perturbations of the signaling pathways involved in mitochondrial biogenesis, as a result of alterations in acid/base balance, alone and in combination with lactate. The combined effects of elevated lactate and lowered pH resulted in greater activation of signaling pathways than the effects of altering either lactate or pH alone. These results support previous findings that propose lactate as an important initiator of signaling cascades for the transcription of genes involved in mitochondrial biogenesis. Further, they also indicate that exercise-induced production of lactate and lowering of pH may be important activators of cell signaling involved in muscle adaptation. In a second study, the effects of artificially lowered pH on pre- and post-exercise expression of regulators and downstream target genes involved in mitochondrial biogenesis were assessed. Participants performed high-intensity interval exercise on two separate occasions, following the ingestion of either ammonium chloride or placebo the day before and on the day of the exercise trial in a randomised, counterbalanced order. The mRNA content of PGC-1α, citrate synthase (CS), cytochrome c (CYT-C), hexokinase II (HKII)and glucose transporter 4 (GLUT4) were determined in biopsies taken from the vastus lateralis muscle before, immediately after exercise and during recovery. Results indicated that acidosis increases the expression of PGC-1α and downstream target genes involved in mitochondrial biogenesis at rest, but suppresses the normal increased gene response following high-intensity exercise. These findings indicate that lowered pH may interfere with exercise-induced mitochondrial biogenesis. Finally an intensive training study was conducted to determine whether impeding exercise-induced acidosis during training alters adaptations in mitochondrial function and performance. Another group of participants undertook a six-week periodised high-intensity interval training programme, a protocol known to produce increases in mitochondrial biogenesis. Participants were matched for aerobic fitness and randomly assigned to one of two different training groups. One group ingested sodium bicarbonate and the other group ingested a placebo prior to each training session. Performance tests, blood and muscle biopsies were collected before and after the six week training period and assessed for changes in aerobic fitness, blood metabolites and muscle markers of mitochondrial function and biogenesis. Both training groups showed substantial changes in performance and physiological measures following the training period, however, suppressing exercise-induced acidosis during training did not significantly improve mitochondrial adaptations or performance in comparison to the placebo condition. However, there was a large degree of individual variation in the response and there were trends towards greater adaptations when exercise-induced acidosis was attenuated. The findings from these series of studies show that signaling cascades are influenced by alterations in acid/base balance, alone and in combination with lactate. Skeletal muscle cell-signalling and gene expression networks are extremely complex with multiple points of regulation and signal divergence. Although at this stage the exact mechanism by which acid/base balance plays a role in altering the signaling mechanisms which regulate mitochondrial function, biogenesis and muscle adaptation are unclear, these studies show that the interaction of altered hydrogen ion concentration and substrate accumulation and utilisation plays an important role in mitochondrial adaptation to training.

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