Strain-specific differences in mitochondrial respiration following short-term dietary restriction in male C57BL/6J and DBA/2 mice

Dietary restriction (DR) is the most consistent dietary intervention to increase lifespan and maintain age-related health across multiple taxa. We examined the effects of short-term (4 weeks) DR on mitochondrial respiration in permeabilised skeletal muscle from male C57BL/6J and DBA/2 mice and discovered significant strain-specific effects. In C57BL/6J mice, DR did not affect mitochondrial volume, as reflected by citrate synthase activity, but enhanced mitochondrial oxidative phosphorylation (Complex I and II OXPHOS). An increase in uncoupled respiration was also observed, along with a significant increase in nuclear PGC-1α protein levels. In contrast, DBA/2 mice displayed higher mitochondrial volume following DR. However, when respiration was normalized to citrate synthase (CS) activity, DBA/2 mice showed a non-significant decrease in Complex I activity but an increase in complex II OXPHOS following DR, resulting in no change in overall OXPHOS/CS. While nuclear PGC-1α protein levels were unaffected by DR in DBA/2 mice, total TFAM protein levels were significantly increased. Consequently, distinctive mitochondrial responses exist following short-term DR between these strains; C57BL/6J mice appear to increase OXPHOS without increasing mitochondrial volume, whereas DBA/2 mice may increase (complex II driven) OXPHOS through increased mitochondrial volume. These findings indicate different mitochondrial responses to short-term DR exist between mouse strains and further highlights the importance of genotype-specific comparisons in the context of interventions that modulate the aging process.