Further to this point, whereas we observed the expected stoichiometry between nuclear and mitochondrial components of the mitochondrial biogenesis pathway in age-matched controls (based upon a close relationship between the nuclear encoded citrate synthase enzyme activity and TFAM protein levels), there was no relationship between these components in COPD, suggesting that even the limited TFAM protein that is available in COPD muscle may be compromised in its function. This evidence concerns the gene CS and chronic obstructive pulmonary disease.