A new mouse model of frailty: the Cu/Zn superoxide dismutase knockout mouse

Abstract

Frailty is a geriatric syndrome that is an important public health problem for the older adults living in the USA. Although several methods have been developed to measure frailty in humans, we have very little understanding of its etiology. Because the molecular basis of frailty is poorly understood, mouse models would be of great value in determining which pathways contribute to the development of frailty. More importantly, mouse models would be critical in testing potential therapies to treat and possibly prevent frailty. In this article, we present data showing that Sod1KO mice, which lack the antioxidant enzyme, Cu/Zn superoxide dismutase, are an excellent model of frailty, and we compare the Sod1KO mice to the only other mouse model of frailty, mice with the deletion of the IL-10 gene. Sod1KO mice exhibit four characteristics that have been used to define human frailty: weight loss, weakness, low physical activity, and exhaustion. In addition, Sod1KO mice show increased inflammation and sarcopenia, which are strongly associated with human frailty. The Sod1KO mice also show alterations in pathways that have been proposed to play a role in the etiology of frailty: oxidative stress, mitochondrial dysfunction, and cell senescence. Using Sod1KO mice, we show that dietary restriction can delay/prevent characteristics of frailty in mice.

Keywords: Cu/Zn superoxide dismutase; Frailty; Inflammation; Oxidative stress; Sarcopenia; Senescence.

Fig. 1

Muscle mass is reduced in Sod1KO mice. a Hindlimb muscle mass of WT and Sod1KO mice over the lifespan of the Sod1KO mice. The age-dependent decrease in muscle mass in the Sod1KO mice, either absolute or relative to body mass, was statistically significant (P < 0.05) as determined by general linear model ANOVA. b Mass in milligrams for individual muscles from 20-month-old WT and Sod1KO mice. G/P gastrocnemius and plantaris, TA/EDL tibialis anterior and extensor digitorum longus, VL vastus lateralis, TB triceps brachii. Blue squares and bars represent WT and red squares and bars represent Sod1KO. Data were analyzed by general linear model ANOVA P < 0.05) with Tukey’s post hoc indicated by an asterisk. Data taken from Muller et al. (2006)

Fig. 2

Muscle strength is reduced in Sod1KO mice. a Grip strength of 9-month-old male WT (n = 7) and Sod1KO mice (n = 8). Data are expressed as mean ± SEM. Data were analyzed by unpaired t test (*P < 0.05). b Maximum isometric specific force (specific Po) values for gastrocnemius muscle of WT and Sod1KO mice during direct muscle stimulation. Data for 1-, 8-, and 20-month-old mice were compared by two-factor (genotype × age) ANOVA. When the ANOVA showed significant differences between groups, individual differences were established by Bonferroni post hoc analyses. Significance was set at P < 0.05 (data taken from Larkin et al. 2011). Blue squares and bars represent WT and red squares and bars represent Sod1KO

Fig. 3

Voluntary wheel running, rotarod performance, and treadmill endurance are reduced in Sod1KO mice. a Voluntary wheel running. WT and Sod1KO mice were individually housed in cages equipped with a zero-resistance running wheel and the average distance run each by each mouse over 16 weeks is shown. *P < 0.05 by ANOVA (data taken from Muller et al. 2006). b Rotarod performance. The average time in seconds that the mice remain on the rotating rod before falling off. *P < 0.05 by ANOVA (data taken from Muller et al. 2006). c Treadmill endurance. The time to run to exhaustion on a treadmill is shown for WT and Sod1KO mice. Significance was established using Student’s t test, ***P < 0.001 (data taken from Jang et al. 2010). Blue bars represent WT and red bars represent Sod1KO

Fig. 4

Measures of inflammation are increased in Sod1KO mice. a NFκB binding activity of nuclear extracts from gastrocnemius muscle data was analyzed using ANOVA (data taken from Vasilaki et al. 2010) and kidney analyzed by two-tailed Student’s t test (data are taken from Zhang et al. (2017)) of WT and Sod1KO mice, *P < 0.05. b The levels of cytokines were measured in the serum collected from WT and Sod1KO mice and data were analyzed by one-tailed Student’s t test, *P < 0.05, **P < 0.01, ***P < 0.001 (data taken from Zhang et al. 2017). Blue bars represent WT and red bars represent Sod1KO

Fig. 5

Oxidative stress, mitochondrial dysfunction, and cell senescence are increased in Sod1KO mice. a Oxidative damage. The level of lipid peroxidation (F₂-isoprostanes) in plasma and whole hind limb skeletal muscle isoprostane. Data were analyzed using ANOVA and Tukey’s post hoc test, *P < 0.05) (data taken from Muller et al. 2006) and DNA oxidation (8-oxo-deoxyguanosine) in liver analyzed by the non-parametric test of ANOVA. Values that are significantly different (P < 0.05) (data taken from Perez VI et al. 2009) from WT and Sod1KO mice. b Mitochondrial dysfunction. The rate of ATP generation and hydrogen peroxide generation by isolated mitochondria from 20-month-old wild-type and Sod1KO mice is shown and the data were analyzed by Student’s t test, *P < 0.05, **P < 0.001 (data taken from Jang et al. 2010). c Cell senescence. The percent β-gal staining cells in kidney (data taken from Zhang et al. 2017) and fat tissue from Sod1KO and WT mice. Data were analyzed by Student’s t test, *P < 0.05. Blue bars represent WT and red bars represent Sod1KO