Long‐term caloric restriction causes dysregulation in cellular redox status in the skeletal muscle of the Cu/Zn‐SOD mutant G93A mouse, an animal model of ALS

Caloric restriction (CR) extends life span due to a reduction in oxidative stress. Paradoxically, long‐term CR hastens clinical onset, disease progression and life span in the G93A mouse, an animal model of ALS, while transiently improving motor performance (Hamadeh et al, 2005; Hamadeh and Tarnopolsky, 2005) . We hypothesized that CR would increase oxidative stress, basal levels of which are heightened in this animal model, partly due to no change in antioxidant enzyme capacity. Indeed, CR increased markers of lipid peroxidation (malondialdehyde‐MDA) in this animal model (Patel et al, 2007) . We aimed to determine the protein content of antioxidant enzymes (Mn‐SOD, Cu/Zn‐SOD) and markers of inflammation (TNF‐α) and anti‐apoptosis (Bcl2) in skeletal muscle of G93A mice. Starting at age 40 d, 27 separately‐caged mice were randomly divided into ad libitum (AL, 14; 7 males) or CR (13; 6 males; 60% of AL). Quadriceps and gastrocnemius were harvested at age 99 d and analyzed using Western blotting techniques. There were no significant differences in Mn‐SOD, Cu/Zn‐SOD, TNF‐α or Bcl2 protein content. However, MDA was positively correlated with red gastrocnemius Cu/Zn‐SOD (r = 0.49, P = 0.017) and male quadriceps TNF‐α (r = 0.69, P = 0.009). We conclude that CR does not alter antioxidant enzyme protein content in the G93A mouse, which in conjunction with an increase in oxidative stress exacerbates disease outcomes in males.