Abstract
Caloric restriction (CR) extends lifespan through a reduction in oxidative stress, delays the onset of morbidity and prolongs lifespan. We previously reported that long-term CR hastened clinical onset, disease progression and shortened lifespan, while transiently improving motor performance in G93A mice, a model of amyotrophic lateral sclerosis (ALS) that shows increased free radical production. To investigate the long-term CR-induced pathology in G93A mice, we assessed the mitochondrial bioenergetic efficiency and oxidative capacity (CS – citrate synthase content and activity, cytochrome c oxidase - COX activity and protein content of COX subunit- I and IV and UCP3- uncoupling protein 3), oxidative damage (MDA – malondialdehyde and PC – protein carbonyls), antioxidant enzyme capacity (Mn-SOD, Cu/Zn-SOD and catalase), inflammation (TNF-α), stress response (Hsp70) and markers of apoptosis (Bax, Bcl-2, caspase 9, cleaved caspase 9) in their skeletal muscle. At age 40 days, G93A mice were divided into two groups: Ad libitum (AL; n = 14; 7 females) or CR (n = 13; 6 females), with a diet equal to 60% of AL. COX/CS enzyme activity was lower in CR vs. AL male quadriceps (35%), despite a 2.3-fold higher COX-IV/CS protein content. UCP3 was higher in CR vs. AL females only. MnSOD and Cu/Zn-SOD were higher in CR vs. AL mice and CR vs. AL females. MDA was higher (83%) in CR vs. AL red gastrocnemius. Conversely, PC was lower in CR vs. AL red (62%) and white (30%) gastrocnemius. TNF-α was higher (52%) in CR vs. AL mice and Hsp70 was lower (62%) in CR vs. AL quadriceps. Bax was higher in CR vs. AL mice (41%) and CR vs. AL females (52%). Catalase, Bcl-2 and caspases did not differ. We conclude that CR increases lipid peroxidation, inflammation and apoptosis, while decreasing mitochondrial bioenergetic efficiency, protein oxidation and stress response in G93A mice.
Highlights
Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterized by the degeneration of motor neurons in the brain and spinal cord and is associated with an increase in oxidative stress [1,2]
We ascertained that using a clinical score of 4 as a proxy measure of endpoint would result in similar conclusions as using a clinical score of 5
We examined the effect of long-term caloric restriction (CR) on markers of mitochondrial bioenergetics, oxidative damage, antioxidant enzyme capacity, inflammation, stress response and apoptosis in the skeletal muscle of G93A mice, an animal model of ALS
Summary
Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterized by the degeneration of motor neurons in the brain and spinal cord and is associated with an increase in oxidative stress [1,2]. One mechanism which has been shown to decrease oxidative stress in animals and extend lifespan is caloric restriction (CR) [3,4,5,6,7]. Transgenic mice that overexpress the mutant human SOD1 gene (G93A mice) are an animal model of ALS and demonstrate elevations in free radical production [8]. When applied to this model, long-term CR hastened clinical onset, disease progression and life span, while transiently improving motor performance [9,10]. Whereas short-term CR hastened clinical onset and shortened lifespan in male, but not female, G93A mice, and hastened disease progression with no effect on paw grip endurance [11]. The objective of this study was to explore how CR in the G93A mouse induces changes at the molecular level in genes involved in oxidative stress management, mitochondrial energetics, inflammation, stress response and apoptosis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
