european college of sport science

Friday, June 26th, 2009
15:15 - 16:45
Invited symposia
IS-BC02 Molecular mechanism controlling mitochondrial biogenesis and function
MITOCHONDRIAL SUBSTRATE OXIDATION: EFFECT OF TRAINING AND TYPE 2 DIABETES.
SAHLIN, K.
GIH, THE SWEDISH SCHOOL OF SPORT AND HEALTH SCIENCES
There is a reciprocal dependency between carbohydrate (CHO) and lipid oxidation and the relative fuel utilization is influenced by a
number of factors including exercise intensity, training status and substrate availability. Control of lipid oxidation occurs at several sites
with mitochondria being one of the most important. A high rate of CHO catabolism may interfere with both the transport of long-chain
fatty acids (LCFA) into mitochondria and with β-oxidation. The supply of lipids is increased in Type 2 diabetes (T2D) due to elevated
blood fatty acid levels and increased intramyocellular contents of triglycerides. Combined with a reduced capacity to oxidize lipids this
leads to accumulation of lipid intermediates, which has been suggested to cause insulin resistance. This presentation will discuss the
interaction between carbohydrate and lipid oxidation at the mitochondrial level, the effect of training and the implication in T2D.
MECHANISMS OF MITOCHONDRIAL BIOGENESIS IN HUMAN SKELETAL MUSCLE
PILEGAARD, H.
UNIVERSITY OF COPENHAGEN
Introduction: Peroxisome proliferator activated receptor gamma (PGC)-1alpha is a transcriptional co-activator regulating the expression of
proteins in many cellular processes including mitochondrial biogenesis and the anti-oxidant defence (Lin et al. 2005). Exercise-induced
regulation of PGC-1alpha expression and activity is suggested to be a key event in training-induced mitochondrial biogenesis.
PGC-1alpha gene regulation
PGC-1alpha transcription and mRNA is increased in human skeletal muscle in response to both short, high-intensity and prolonged lowintensity
exercise, and PGC-1alpha mRNA is markedly induced in both the glycolytic triceps muscle and the more oxidative vastus lateralis
muscle. The exercise-induced PGC-1alpha mRNA increase in human skeletal muscle is determined by the relative rather than the absolute
exercise intensity. The PGC-1alpha mRNA response to a single exercise bout does not seem to be influenced by muscle glycogen
levels prior to exercise, but to be modulated by the metabolic status in recovery from exercise.
Cell culture studies indicate that calcium signalling through both CAMK and calcineurin as well as ROS-induced signalling may play a
major role in regulating the expression of PGC-1alpha in skeletal muscle.
PGC-1alpha protein
PGC-1alpha protein is in western blotting detected at a molecular weight of about 115 kD. But analyses of endogenous PGC-1alpha protein
should be done with utmost caution, as the amount of endogenous PGC-1a in skeletal muscle is very low.
PGC-1alpha mediated regulation of mitochondrial proteins
The late mRNA responses to exercise for genes encoding mitochondrial proteins in human skeletal muscle are in accordance with the
suggestion that exercise-induced regulation of PGC-1alpa expression and/or activity may mediate the induction of genes encoding
mitochondrial proteins.
In mice skeletal muscle, PGC-1alpha is required for the beneficial effect of exercise in preventing an age-associated decline in cytochrome
c and superoxide dismutase 2 protein expression. In addition, findings in mice suggest that although AMPK is not needed for
exercise-induced PGC-1alpha gene regulation, AMPK mediated regulation of PGC-1alpha seems to play an important role in regulating
the expression of mitochondrial proteins.
Reference
Lin J, Handschin C, Spiegelman BM. Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab 1: 361-370, 2005.
MECHANISMS OF MITOCHONDRIAL BIOGENESIS IN AGING MUSCLE
HOOD, D.
YORK UNIVERSITY
It is well known that mitochondrial biogenesis in muscle can occur as a result of regular exercise. However, the mechanisms underlying
organelle biogenesis are not fully established. In addition, whether similar mechanisms exist in aging muscle remains controversial.
Evidence suggests that the initial signals generated by exercising muscle which provoke gene expression leading to mitochondrial biogenesis
are related to changes in intracellular calcium, reactive oxygen species, and AMP kinase activity. Activation of AMP kinase leads
to the transcription of PGC-1α, an important regulator of the expression of many nuclear genes encoding mitochondrial proteins. In
addition, chronic exercise increases the import of proteins into the organelle. This is a result of an increased expression of protein import
machinery components. During the aging process, mitochondrial content in muscle declines, and this is reflected in a reduced endurance
performance. The decrease in mitochondrial content is due in part to a reduced transcriptional drive, since PGC-1α levels are markedly
reduced, particularly in slow-twitch muscle fibers. In addition, in response to a standardized acute contractile activity paradigm,
signaling kinase activation is increased to a lesser degree than in muscle from young animals. This contributes to the reduced adaptation
of aged muscle to regular exercise, consisting of attenuated increases in the expression of biogenesis regulatory proteins of transcription
and protein import, reduced increases in mitochondrial enzymes, and lesser improvements in endurance performance. These data
suggest that activation of the mitochondrial biogenesis pathway by exercise is down-regulated with age. Despite this, adaptive responses
to exercise can still occur in aging muscle, leading to reduced fatiguability and improved quality of life. Further studies are required
to determine the underlying basis for the attenuated adaptive response of aging muscle to exercise.
OSLO/NORWAY, JUNE 24-27, 2009 467