Long‐term caloric restriction decreases mitochondrial bioenergetic efficiency in the skeletal muscle of the Cu/Zn‐SOD mutant male G93A mouse, an animal model of ALS

Long‐term caloric restriction (CR) attenuates oxidative stress, delays the onset of morbidity and prolongs life span. Contrarily, we previously reported that long‐term CR transiently improved motor performance but hastened clinical onset, shortened life span, and increased malondialdehyde (marker of oxidative damage) in the male G93A mouse, a transgenic animal model of amyotrophic lateral sclerosis (ALS) ( Hamadeh et al., 2005; Patel et al., 2007 ). We hypothesized that CR would decrease mitochondrial oxidative capacity and the adaptive increase in antioxidant enzyme response in G93A mice. At age 40 d, 24 separately caged G93A mice were randomly divided into ad libitum (AL, n = 12; 6 males) or CR (n = 12; 6 males; 60% of AL). We measured protein content of TCA cycle (citrate synthase‐CS), electron transport chain (COX subunit–IV), and antioxidant enzymes (Mn‐SOD, Cu/Zn‐SOD), as well as CS and COX enzyme activity in the quadriceps at age 99 d. CR decreased COX/CS enzyme activity in males (35%, P = 0.034) despite a 2.3 fold increase in COX‐IV/CS protein content (P = 0.059), indicative of impaired mitochondrial oxidative capacity. Mn‐SOD and Cu/Zn‐SOD protein content remained unchanged. We conclude that CR increases the content of mitochondrial respiratory chain to compensate for its reduced bioenergetic efficiency, which in conjunction with unaltered antioxidant capacity and increased oxidative damage could exacerbate disease outcomes in male G93A mice. (Supported by Hamilton Health Sciences Foundation and NSERC Canada)