Caloric Restriction Shortens Lifespan through an Increase in Lipid Peroxidation, Inflammation and Apoptosis in the G93A Mouse, an Animal Model of ALS

• Published in: PloS one 2010-02, Vol.5 (2), p.e9386-e9386
• Main Authors: Patel, Barkha P, Safdar, Adeel, Raha, Sandeep, Tarnopolsky, Mark A, Hamadeh, Mazen J
• Format: Article
• Language: English
• Subjects: Age; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - physiopathology; Analysis; animal disease models; Animal models; animal proteins; Animals; Antioxidants; Apoptosis; Apoptosis - physiology; BAX protein; Bcl-2 protein; Biochemistry; Blotting, Western; Body Weight - physiology; Brain research; Caloric Restriction - adverse effects; Carbonyl compounds; Carbonyls; Caspase; Caspase-9; Catalase; Catalase - metabolism; Cell Biology; Cell Biology/Cellular Death and Stress Responses; Citrate synthase; Copper; Cytochrome; Cytochrome c; Cytochrome-c oxidase; Dietary restrictions; Disease Models, Animal; Eating - physiology; electron transport chain; Electron Transport Complex IV - metabolism; energy metabolism; Enzymatic activity; Enzyme activity; Female; Females; Fitness training programs; Food; Heat shock proteins; Hsp70 protein; Humans; Inflammation; Inflammation - etiology; Inflammation - metabolism; Inflammation - physiopathology; Kinesiology; Laboratories; Life span; Lipid peroxidation; Lipid Peroxidation - physiology; longevity; Longevity - physiology; low calorie diet; Male; Males; Malondialdehyde; Manganese; Medical research; Mice; Mice, Inbred Strains; Mice, Transgenic; Mitochondria; Mitochondria - metabolism; mitochondrial bioenergetic efficiency; Molecular Biology; Morbidity; Motor Activity - physiology; Motor task performance; Musculoskeletal system; nervous system diseases; Oxidases; Oxidation; Oxidative stress; Pathology/Molecular Pathology; Pediatrics; Peroxidation; Physiology; Physiology/Muscle and Connective Tissue; Researchers; Rodents; Sex Factors; Short term; signs and symptoms (animals and humans); Skeletal muscle; Studies; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Superoxides; Survival Analysis; Tumor Necrosis Factor-alpha - metabolism; Vertebra; Vertebrae; Zinc
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0009386

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.