Abstract
The accumulation of oxidative damage is strongly linked to age-dependent declines in cell function, but the contribution of oxidative damage to morbidity is still debated. Many organisms seem to tolerate oxidative damage, and the extension of health span and life span by augmenting antioxidant activity has been inconsistent. Here we use the Drosophila model system to investigate the relationship among oxidative stress, health span, and life span. The oxidation-dependent dissociation of the Calstabin protein from the ryanodine receptor has been shown to result in reduced muscle function in mammals. The S107 molecule is able to reestablish this binding resulting in improved muscle function. We find that S107 is able to restore motor function in aging Drosophila to young levels, and this effect of S107 is absent in calstabin (FK506-BP2) mutants. Interestingly, FK506-BP2 mutant flies have reduced sensitivity to the effects of age and oxidative stress on motor function between 7 and 35 days of age. Muscle expression of FK506-BP2 in FK506-BP2 mutants completely restores the sensitivity of motor function to both age and oxidative stress, supporting the idea that the age-dependent decline in motor function in Drosophila requires FK506-BP2 function within the muscle. Although FK506-BP2 mutant flies are found to have less sensitivity to oxidative stress, FK506-BP2 mutants do not live longer than wild type. These results demonstrate that the deleterious effects of oxidation on motor function early in life are the result of a singular event that does not compromise survival.
Highlights
The accumulation of oxidative damage is strongly linked to age-dependent declines in cell function, but the contribution of oxidative damage to morbidity is still debated
S107 Restores Muscle Function during Aging in Drosophila— To investigate the effects of age on muscle function in Drosophila, we utilized a simple motor reflex in flies known as the proboscis extension reflex (PER) [35]
Velocities decline continuously throughout the life span, we observe an abrupt change in the linear displacement of the proboscis between 35 and 42 days of age (Fig. 1E). Because this change in displacement correlates strongly with the age-dependent potentiation of neurotransmitter release we previously demonstrated at the cibarial muscle 9 neuromuscular junction (CM9 NMJ) [36], we believe that this change in displacement is related to this change in motor neuron output and not muscle physiology
Summary
RyR, ryanodine receptor; PER, proboscis extension reflex; CM9, cibarial muscle 9; NMJ, neuromuscular junction; EJP, endplate junctional potential; mEJP, miniature endplate junctional potential; 4-HNE, 4-hydroxynonenal; DNPH, 2,4-dinitrophenylhydrazine; NMR, naked mole rat; ANOVA, analysis of variance. In skeletal muscle is an important cause of compromised muscle function during aging [34]
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