The single nucleotide polymorphism Gly482Ser in the PGC-1α gene impairs exercise-induced slow-twitch muscle fibre transformation in humans.

PGC-1α (peroxisome proliferator-activated receptor γ co-activator 1α) is an important regulator of mitochondrial biogenesis and a master regulator of enzymes involved in oxidative phosphorylation. Recent evidence demonstrated that the Gly482Ser single nucleotide polymorphism (SNP) in the PGC-1α gene affects insulin sensitivity, blood lipid metabolism and binding to myocyte enhancer factor 2 (MEF2). Individuals carrying this SNP were shown to have a reduced cardiorespiratory fitness and a higher risk to develop type 2 diabetes. Here, we investigated the responses of untrained men with the Gly482Ser SNP to a 10 week programme of endurance training (cycling, 3 x 60 min/week, heart rate at 70-90% VO2peak). Quantitative data from analysis of biopsies from vastus lateralis muscle revealed that the SNP group, in contrast to the control group, lacked a training-induced increase in content of slow contracting oxidative fibres. Capillary supply, mitochondrial density, mitochondrial enzyme activities and intramyocellular lipid content increased similarly in both groups. These results indicate that the impaired binding of MEF2 to PGC-1α in humans with this SNP impedes exercise-induced fast-to-slow muscle fibre transformation.

Superior endurance performance in aging mountain runners.

BACKGROUND: Oxygen uptake at the anaerobic threshold (VO(2)AT) is considered as the main determinant for endurance performance in humans. Endurance performance steeply decreases with aging but seems to be kept exceedingly high in elite mountain runners. METHODS: To obtain the age- and gender-related upper limits of endurance performance in this sport, we analyzed the results of the World Masters Athletic Championships in Mountain Running 2007. Additionally, to investigate the relationship between the individual VO(2)AT values and running times, laboratory tests were performed in 10 mountain runners. RESULTS: The World Championships race times of the first 5 finishers of the 5-year age groups did not differ significantly from 35 to 49 years. The corresponding mean (+/- SD) values of the VO(2)AT were 68.0 +/- 1.7 ml/min/kg in males and 58.1 +/- 1.9 ml/min/kg in females. In the following age groups up to 70+ there was a decrease in the VO(2)AT of 29.1% in males and 33.9% in females. CONCLUSION: Thus, at the beginning of the 3rd millennium, elite mountain runners demonstrate that VO(2)AT and probably also VO(2max) may be held at top levels in humans up to the age of 45-49 years in both sexes. Despite the following decrease, endurance capacity remains about 3.5-fold higher in elite mountain runners up to 70+ years when compared to their untrained peers.

A novel sporadic mutation G14739A of the mitochondrial tRNA(Glu) in a girl with exercise intolerance.

We describe a 7-year-old girl who presented with loss of appetite, weakness and excercise intolerance. Enzyme investigation of the respiratory chain in muscle tissue revealed a combined complex I, III and IV deficiency. A novel heteroplasmic G-->A exchange at nucleotide position 14739 was found in the MTTE gene of the tRNA glutamic acid. The mutation load in muscle was 72%, urine sediment 38%, blood 31% and fibroblasts 29% and it correlated with COX-negative fibres. Our patient presented with a predominantly myopathic phenotype. The G14739A mutation is the third reported in the mitochondrial tRNA glutamic acid gene, and it occurred in a sporadic case.

Reduced respiratory control with ADP and changed pattern of respiratory chain enzymes as a result of selective deficiency of the mitochondrial ATP synthase.

The F(o)F(1)-ATPase, a multisubunit protein complex of the inner mitochondrial membrane, produces most of the ATP in mammalian cells. Mitochondrial diseases as a result of a dysfunction of ATPase can be caused by mutations in mitochondrial DNA-encoded ATPase subunit a or rarely by an ATPase defect of nuclear origin. Here we present a detailed functional and immunochemical analysis of a new case of selective and generalized ATPase deficiency found in an Austrian patient. The defect manifested with developmental delay, muscle hypotonia, failure to thrive, ptosis, and varying lactic acidemia (up to 12 mmol/L) beginning from the neonatal period. A low-degree dilated cardiomyopathy of the left ventricle developed between the age of 1 and 2 y. A >90% decrease in oligomycin-sensitive ATPase activity and an 86% decrease in the content of the ATPase complex was found in muscle mitochondria. It was associated with a significant decrease of ADP-stimulated respiration of succinate (1.5-fold) and respiratory control with ADP (1.7-fold) in permeabilized muscle fibers, and with a slight decrease of the respiratory chain complex I and compensatory increase in the content of complexes III and IV. The same ATPase deficiency without an increase in respiratory chain complexes was found in fibroblasts, suggesting a generalized defect with tissue-specific manifestation. Absence of any mutations in mitochondrial ATP6 and ATP8 genes indicates a nuclear origin of the defect.