Calorie restriction in mice overexpressing UCP3: Evidence that prior mitochondrial uncoupling alters response

Calorie restriction (CR) without malnutrition is the only intervention to consistently increase lifespan in all species tested, and lower age-related pathologies in mammals including humans. It has been suggested that uncoupling of mitochondrial oxidative phosphorylation, using chemical uncouplers, mimics CR, and that overlapping mechanisms underlie the phenotypic changes induced by uncoupling and CR. We aimed to critically assess this using a unique mouse model of skeletal muscle-targeted UCP3-induced uncoupling (UCP3Tg), and focused our studies mainly on skeletal muscle mitochondria. Compared to ad libitum fed Wt mice, skeletal muscle mitochondria from ad libitum fed UCP3Tg mice showed higher basal uncoupling and lower H2O2 emission, with unchanged maximal oxidative phosphorylation, and mitochondrial content. UCP3Tg CR mice showed some tendency for differential adaptation to CR, with lowered H+ leak conductance and evidence for higher H2O2 emission from skeletal muscle mitochondria following 2 weeks CR, and failure to lower H2O2 emission after 1 month CR. Differential adaptation was also apparent at the whole body level: while UCP3Tg CR mice lost as much weight as Wt CR mice, the proportion of muscle lost was higher in UCP3Tg mice. However, a striking outcome of our studies was the absence of change with CR in many of the parameters of mitochondrial function and content that we measured in mice of either genotype. Overall, our study raises the question of whether CR can consistently modify skeletal muscle mitochondria; alterations with CR may only be apparent under certain conditions such as during the 2 wk CR intervention in the UCP3Tg mice.

► We test if similar mechanisms drive adaptation to mitochondrial uncoupling and CR.
► We use a mouse model of skeletal muscle-targeted UCP3 overexpression (UCP3Tg).
► UCP3Tg CR mice adapted differently to CR following both 2 weeks and 1 month CR.
► Strikingly, muscle mitochondria of control mice changed minimally with CR.
► We conclude that uncoupling and CR depend on distinct mechanisms.