Exercise and regulation of mitochondrial biogenesis factors in human skeletal muscle
Author: Norrbom, Jessica
Date: 2008-06-13
Location: Farmakologens föreläsningssal, Nanna Svartz väg 2, Karolinska Institutet
Time: 09.00
Department: Institutionen för fysiologi och farmakologi / Department of Physiology and Pharmacology
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Thesis (2.446Mb)
Abstract
Regular physical activity has many positive implications on health and performance, such as lowered risk for premature death, improved glucose metabolism and cardiovascular function as well as endurance capacity. Even a single bout of exercise is enough stimulus to change expression of many skeletal muscle genes. When exercise is performed regularly, the added effects of many bouts lead to changes of muscle phenotype. One of the most profound changes in skeletal muscle is an increased mitochondrial density. This contributes to an improved oxidative capacity, enhanced aerobic and endurance performance as well as to the positive health effects associated with regular endurance training. The exercise-induced skeletal muscle adaptations have been suggested to be influenced by many stimuli, e.g. changes in calcium concentration, metabolic alterations and oxygen tension. The understanding of the regulatory pathways in vivo, especially in humans, is largely lacking.
This thesis aimed to further explore the exercise-regulation of selected mitochondrial biogenesis factors in human skeletal muscle. The influence of a single bout of exercise, endurance training and activity level on the co-activators PGC-1alpha and -1beta and the mitochondrial transcription factors TFAM, TFB1M and TFB2M was studied. Additional aims were to explore the relative importance of signaling pathways suggested to regulate PGC-1 in exercising skeletal muscle and the role of enhanced metabolic perturbation. A one-legged knee extension model was used where blood flow is restricted and metabolic perturbation induced in a controlled fashion. Also, a comparison was made between elite athletes, moderately active and spinal cord injured.
A single bout of exercise with enhanced metabolic perturbation induced both PGC-1alpha mRNA expression and AMPK activation (phosphorylation) more than exercise with normal blood flow. Even though the calcineurin and p38 signaling pathways were activated with exercise, there was no difference in the increase between exercise conditions why they do not seem to have dominant roles in the regulation of exercise-induced PGC-1alpha expression. PGC-1beta mRNA increased with normal blood flow exercise, suggesting differential regulation of the two coactivators. TFAM protein, but not mRNA, levels were increased after 4 weeks of endurance training. Also, elite athletes had a higher TFAM protein level compared to moderately active. TFB1M and TFB2M mRNA, but not protein, levels were higher in elite athletes than in moderately active, and increased with endurance training in the leg that exercised with restricted blood flow.
It is concluded that exercise transcriptionally activates PGC-1alpha and -1beta but their regulation seems to be different. It is indicated that AMPK has a greater influence on exercise-induced PGC-1alpha mRNA compared to calcineurin and p38. The involvement of TFAM in exercise-induced mitochondrial biogenesis is supported and TFAM is most likely regulated through protein stabilization. Conversely, pre-translational changes occur for the TFB factors. Exercise-induced expression of PGC-1alpha most likely contributes to the increase in TFAM protein which in turn drives mitochondrial biogenesis. In the future, studies are needed to better establish the regulatory links between PGC-1alpha and mitochondrial regulatory factors, and to evaluate the temporal patterns between these factors. Such knowledge would further explain how exercise leads to mitochondrial biogenesis.
This thesis aimed to further explore the exercise-regulation of selected mitochondrial biogenesis factors in human skeletal muscle. The influence of a single bout of exercise, endurance training and activity level on the co-activators PGC-1alpha and -1beta and the mitochondrial transcription factors TFAM, TFB1M and TFB2M was studied. Additional aims were to explore the relative importance of signaling pathways suggested to regulate PGC-1 in exercising skeletal muscle and the role of enhanced metabolic perturbation. A one-legged knee extension model was used where blood flow is restricted and metabolic perturbation induced in a controlled fashion. Also, a comparison was made between elite athletes, moderately active and spinal cord injured.
A single bout of exercise with enhanced metabolic perturbation induced both PGC-1alpha mRNA expression and AMPK activation (phosphorylation) more than exercise with normal blood flow. Even though the calcineurin and p38 signaling pathways were activated with exercise, there was no difference in the increase between exercise conditions why they do not seem to have dominant roles in the regulation of exercise-induced PGC-1alpha expression. PGC-1beta mRNA increased with normal blood flow exercise, suggesting differential regulation of the two coactivators. TFAM protein, but not mRNA, levels were increased after 4 weeks of endurance training. Also, elite athletes had a higher TFAM protein level compared to moderately active. TFB1M and TFB2M mRNA, but not protein, levels were higher in elite athletes than in moderately active, and increased with endurance training in the leg that exercised with restricted blood flow.
It is concluded that exercise transcriptionally activates PGC-1alpha and -1beta but their regulation seems to be different. It is indicated that AMPK has a greater influence on exercise-induced PGC-1alpha mRNA compared to calcineurin and p38. The involvement of TFAM in exercise-induced mitochondrial biogenesis is supported and TFAM is most likely regulated through protein stabilization. Conversely, pre-translational changes occur for the TFB factors. Exercise-induced expression of PGC-1alpha most likely contributes to the increase in TFAM protein which in turn drives mitochondrial biogenesis. In the future, studies are needed to better establish the regulatory links between PGC-1alpha and mitochondrial regulatory factors, and to evaluate the temporal patterns between these factors. Such knowledge would further explain how exercise leads to mitochondrial biogenesis.
List of papers:
I. Norrbom J, Sundberg CJ, Ameln H, Kraus WE, Jansson E, Gustafsson T (2004). PGC-1alpha mRNA expression is influenced by metabolic perturbation in exercising human skeletal muscle. J Appl Physiol. 96(1): 189-94. Epub 2003 Sep 12
Pubmed
II. Norrbom J, Rundqvist H, Österlund T, Sundberg CJ, Gustafsson T (2008). PGC-1alpha and upstream regulators in human skeletal muscle in response to exercise. [Submitted]
III. Krämer DK, Ahlsén M, Norrbom J, Jansson E, Hjeltnes N, Gustafsson T, Krook A (2006). Human skeletal muscle fibre type variations correlate with PPAR alpha, PPAR delta and PGC-1 alpha mRNA. Acta Physiol (Oxf). 188(3-4): 207-16.
Pubmed
IV. Bengtsson J, Gustafsson T, Widegren U, Jansson E, Sundberg CJ (2001). Mitochondrial transcription factor A and respiratory complex IV increase in response to exercise training in humans. Pflugers Arch. 443(1): 61-6.
Pubmed
V. Norrbom J, Gustafsson T, Rundqvist H, Wallman S, Jansson E, Sundberg CJ (2008). Expression of mitochondrial transcription factors TFAM, TFB1M and TFB2M in response to training in human skeletal muscle. [Submitted]
I. Norrbom J, Sundberg CJ, Ameln H, Kraus WE, Jansson E, Gustafsson T (2004). PGC-1alpha mRNA expression is influenced by metabolic perturbation in exercising human skeletal muscle. J Appl Physiol. 96(1): 189-94. Epub 2003 Sep 12
Pubmed
II. Norrbom J, Rundqvist H, Österlund T, Sundberg CJ, Gustafsson T (2008). PGC-1alpha and upstream regulators in human skeletal muscle in response to exercise. [Submitted]
III. Krämer DK, Ahlsén M, Norrbom J, Jansson E, Hjeltnes N, Gustafsson T, Krook A (2006). Human skeletal muscle fibre type variations correlate with PPAR alpha, PPAR delta and PGC-1 alpha mRNA. Acta Physiol (Oxf). 188(3-4): 207-16.
Pubmed
IV. Bengtsson J, Gustafsson T, Widegren U, Jansson E, Sundberg CJ (2001). Mitochondrial transcription factor A and respiratory complex IV increase in response to exercise training in humans. Pflugers Arch. 443(1): 61-6.
Pubmed
V. Norrbom J, Gustafsson T, Rundqvist H, Wallman S, Jansson E, Sundberg CJ (2008). Expression of mitochondrial transcription factors TFAM, TFB1M and TFB2M in response to training in human skeletal muscle. [Submitted]
Issue date: 2008-05-23
Rights:
Publication year: 2008
ISBN: 978-91-7409-010-9
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