TFAM and mitochondrial disease: Interestingly, single fiber observations of mitochondrial biogenesis within these COX−/SDH+ fibers have revealed an upregulation of mtDNA copy number and TFAM protein levels [27–29] compared to oxidative-normal fibers, and at the whole muscle level, this is associated with activation of the mitochondrial biogenesis signaling cascade [30], reflecting an attempted compensatory response to the cellular oxidative deficiency, noting that this response at the single fiber level occurs despite the very sedentary behavior typical of patients with mitochondrial disease [31].