title: Caloric restriction shortens lifespan through an increase in lipid peroxidation, inflammation and apoptosis in the G93A mouse, an animal model of ALS.
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-alpha), 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-alpha 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.
authors.affiliation: School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada.
authors.forename: Barkha P
authors.initials: BP
authors.lastname: Patel
authors.forename: Adeel
authors.initials: A
authors.lastname: Safdar
authors.forename: Sandeep
authors.initials: S
authors.lastname: Raha
authors.forename: Mark A
authors.initials: MA
authors.lastname: Tarnopolsky
authors.forename: Mazen J
authors.initials: MJ
authors.lastname: Hamadeh
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D001835:Body Weight / Q000502:physiology; D031204:Caloric Restriction / Q000009:adverse effects*; D002374:Catalase / Q000378:metabolism; D004195:Disease Models, Animal; D004435:Eating / Q000502:physiology; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D015227:Lipid Peroxidation / Q000502:physiology*; D008136:Longevity / Q000502:physiology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D009043:Motor Activity / Q000502:physiology; D012737:Sex Factors; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D014409:Tumor Necrosis Factor-alpha; D002374:Catalase; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D003576:Electron Transport Complex IV