Alterations in brain glycogen levels influence life-history traits and reduce the lifespan in female Drosophila melanogaster

Abstract

Sexual dimorphism in lifespan, wherein females outlive males, is evident across all animal taxa. The longevity difference between sexes is controlled by multiple physiological processes with complex relationships to one another. In recent years, glycogen, the storage form of glucose, has been shown to cause rapid aging upon forced synthesis in healthy neurons. Glycogen in the form of corpora amylacea in the aging brain is also widely reported. While these studies did suggest a novel role for glycogen in aging, most of them have focused on pooled samples, and have not looked at sex-specific effects, if any. Given the widespread occurrence of sex-biased expression of genes and the underlying physiology, it is important to look at the sex-specific effect of metabolic processes. In the present study, using transgenic fly lines for the human glycogen synthase, we investigated the sex-specific effect of glycogen on stress resistance, fitness, and survival. We demonstrate that Drosophila females with altered levels of glycogen in the brain display a shortened lifespan, increased resistance to starvation, and higher oxidative stress than male flies. The present study thus provides a novel insight into the sex-specific effect of glycogen in survival and aging and how differences in metabolic processes could contribute to sex-specific traits.

Increase in brain glycogen levels ameliorates Huntington's disease phenotype and rescues neurodegeneration in Drosophila

“…The fly lines expressing the 20 polyglutamine (polyQ) repeats ( UAS-Q20 ) ( Kazemi-Esfarjani and Benzer, 2000 ), the mutant line expressing the 93 polyQ repeats encoded by exon 1 of the HTT gene ( UAS-httex1Q93 or UAS-Q93 ) ( Kazemi-Esfarjani and Benzer, 2000 ), the pan-neuronal driver line elav-Gal4 C155 ( Yao et al, 1993 ) and the eye-specific driver line that expresses in the eye-imaginal discs of the larvae and in the adult eye ( GMR-Gal4 ) ( Kumar et al, 2014 ) were kindly provided by Prof. Pradip Sinha (IIT Kanpur, India). Transgenic lines expressing the wild-type form of GS ( UAS-hMGS-wt ), the constitutively active form ( UAS-hMGS-9A ) and the GS-knockdown line ( UAS-GSRNAi ) were a kind gift from Prof. Joan J. Guinovart (IRB, Barcelona, Spain), and have been described in previous studies ( Duran et al, 2012 ; Sinadinos et al, 2014 ; Sheshadri et al, 2021 ). Males of all the transgenic lines used in the study were crossed with virgins of elav-Gal4 C155 and GMR-Gal4 to drive their expression in the fly brain and the eye-imaginal discs, respectively.…”

“…Glycogen synthase (GS) activity was measured using Danforth's spectrophotometric method as previously described ( Danforth, 1965 ; Sheshadri et al, 2021 ). Briefly, fly whole-head lysates were added to a reaction mixture comprising 48 mM Tris pH 8.2, 12.4 mM MgCl 2 , 1 mM EDTA, 2.4 mM 2-mercaptoethanol, 3.63 mM UDPG.2Na hydrate and 9.7 mM glucose-6-phosphate.…”

“…The glycogen content in the fly heads was measured using the protocol described earlier ( Sheshadri et al, 2021 ). Briefly, for each genotype twenty fly heads were homogenized in 100 µl of 30% KOH solution and boiled at 100°C for 20 min.…”

“…Intriguingly, unlike liver and muscle, which store significant amounts of glycogen, the glycogen content in the brain is minimal, the majority of it primarily being stored in astrocytes ( Pellerin and Magistretti, 1994 ; Obel et al, 2012 ; Saez et al, 2014 ). Thus, excessive accumulation of brain glycogen in pathological neurodegenerative conditions indicates the alterations in the glycogen metabolic pathways, which could either be the cause or the consequence of abnormal neuronal physiology and function ( Rai and Ganesh, 2019 ; Onkar et al, 2020 ; Sheshadri et al, 2021 ).…”

“…Abnormal glycogen aggregates, in the form of corpora amylacea, are commonly observed in the aging brain ( Augé et al, 2017 ; Riba et al, 2021a , b ), and ectopic glycogen build-up in healthy neurons of mouse and fly models results in accelerated aging and motor impairment ( Duran et al, 2012 ). Recently, changes in brain glycogen levels have also been shown to modify sex-specific survival in Drosophila melanogaster ( Sheshadri et al, 2021 ). Abnormal glycogen aggregates or polyglucosan bodies have also been detected in the degenerating brain of mouse models and in brains of humans diagnosed with neurodegenerative disorders ( Trivedi et al, 2003 ; Rohn, 2015 ; Rai et al, 2018 ), although their significance is yet to be understood.…”