Extension of Health Span and Life Span in Drosophila by S107 Requires the calstabin Homologue FK506-BP2

Abstract

Edited by Jeffrey PessinThe 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.

Dynamics expression of DmFKBP12/Calstabin during embryonic early development of Drosophila melanogaster

“…The above inspection demonstrated that the Drosophila DmFKBP12 expression was examied at both translation and transcription levels. Our data extend the detected expression of DmFKBP12 from adult Drosophila [20] to very early embryonic syncytial blastoderm stage of its development with multiple nuclei of first 13 mitosis after fertilization [34].…”

“…However, very limited information documented from published data about insect RyR regulator DmFKBP12. The DmFKBP12 was identified on function of extension both health and life spans using loss of DmFKBP12 gene function model in Drosophila muscle [20]. This work claimed that the absence of DmFKBP12 in the cytoplasmic of DmFKBP12 mutant muscle dissociated RyR from response to oxidation and resulted in earlier aging.…”

“…Because lack of HmFKBP12 generating the newborn defects with the cerebral edema and cardiac arrhythmia [18], and FKBP12 overexpression led to lethal defect of arrhythmic pathology [19], a critical function of DmFKBP12 is expected on Drosophila physiological role. Recently, the data from DmFKBP12 mutant (also known as Calstabin and FK506 - BP2 ) demonstrated that DmFKBP12 is necessary for S107 to play its critical role on extension of both health and life span against oxidative stress, and DmRyR is essential for larval development in Drosophila flies [20, 21].…”

Sarcoplasmic reticulum Ca2+ decreases with age and correlates with the decline in muscle function in Drosophila

“…However, recent studies have indicated that in mammalian skeletal muscle, RyR1 might be the physical substrate of an increased leak, especially in aged animals (Andersson et al, 2011;Bellinger et al, 2008;Jiménez-Moreno et al, 2008), where post-translational modifications of RyR1 and/or dissociation of the stabilizing protein Calstabin 1 can increase the resting conductance of the leak channel (Andersson et al, 2011;Mei et al, 2013). A RyR-mediated leakiness that increases with aging has been postulated in muscle for mice (Andersson et al, 2011) and flies (Kreko-Pierce et al, 2016), and even in human Blymphocytes, where RyR leakiness can be used as a likelihood biomarker for congestive heart failure (Kushnir et al, 2018). This view contrasts with data reported in neural tissues, which have been mainly studied in mouse models, and where loss of Ca 2+ homeostasis in the cytosolic Ca 2+ has been frequently proposed (Alzheimer's Association Calcium Hypothesis Workgroup, 2017; Thibault et al, 2007).…”

Transcriptomics of aged Drosophila motor neurons reveals a matrix metalloproteinase that impairs motor function

“…The aging of the nervous system is manifested not only in the decline of cognition and memory, but also in the progressive decline of motor coordination and muscle function (Doherty, ). These declines in motor function have been observed throughout the animal kingdom including in humans, rodents, and insects (Jang & Van Remmen, ; Seidler et al., ) (Gargano et al., ; Kreko‐Pierce et al., ). In mammals, much of the motor decline is due to muscle fiber loss and declining fiber contractility, but altered motor neuron (MN) function also contributes (Edstrom et al., ).…”