Dataset Information

Sex-specific Phosphoproteome Responses to Calorie Restriction and Insulin in Skeletal Muscle from Older Rats

ABSTRACT: Aging impairs skeletal muscle insulin sensitivity, yet the underlying molecular mechanisms remain incompletely understood. Here, we examined how short-term caloric restriction (CR) alters muscle insulin action and signaling in aged rats (22 months old) of both sexes. After 8 weeks of CR or ad libitum feeding, we assessed insulin-stimulated glucose uptake (ISGU) ex vivo and performed deep phosphoproteomic profiling. CR enhanced ISGU in both sexes, with a more pronounced effect in females. Insulin-regulated phosphoproteomic responses were concordant between males and females, yet females exhibited more robust and widespread phosphorylation changes, potentially explaining their greater ISGU. CR induced extensive remodeling of basal muscle phosphorylation, particularly within structural and contractile pathways. Personalized phosphoproteomic analysis identified insulin-responsive sites on Leiomodin-1 (Lmod1) and EH domain-binding protein 1-like protein 1 (Ehbp1l1) that correlated with ISGU across individuals. Notably, Lmod1demonstrated strong genetic association with glycemic traits in humans, and several regulated sites overlapped with phosphosites observed in human clamp studies, reinforcing their translational relevance. Collectively, these findings reveal sex-dependent and diet-sensitive phosphosignaling mechanisms that modulate muscle insulin responsiveness during aging and nominate candidate regulatory nodes for future study.

INSTRUMENT(S):

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Skeletal Muscle

SUBMITTER: Sean Humphrey

LAB HEAD: Sean Humphrey

PROVIDER: PXD064514 | Pride | 2025-11-24

REPOSITORIES: Pride

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			Action	DRS
	20220225_EXP1_SeHu_Cartee_EasyPhos_M-AL-H56-1L-1.raw	Raw
	20220225_EXP1_SeHu_Cartee_EasyPhos_M-AL-H56-1L-2.raw	Raw
	20220225_EXP1_SeHu_Cartee_EasyPhos_M-AL-H56-1R-1.raw	Raw
	20220225_EXP1_SeHu_Cartee_EasyPhos_M-AL-H56-1R-2.raw	Raw
	20220225_EXP1_SeHu_Cartee_EasyPhos_M-AL-H56-2L-1.raw	Raw

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Sex-specific phosphoproteome responses to calorie restriction and insulin in skeletal muscle from older rats.

Wang Haiyan H Madsen Søren S Needham Elise J EJ Humphrey Sean J SJ Zheng Amy A Arias Edward B EB Stöckli Jacqueline J Cutler Harry B HB James David E DE Cartee Gregory D GD

The journals of gerontology. Series A, Biological sciences and medical sciences 20251101 12

Calorie restriction (CR; calorie intake reduced by ∼20%-40% below ad libitum, AL, intake) potentiates skeletal muscle insulin sensitivity during old age by incompletely understood mechanisms. We aimed to identify CR-induced changes in muscle insulin signaling that may explain this enhanced sensitivity. We examined how CR (65% of AL intake for 8-weeks) alters muscle insulin action and signaling in aged rats (24-month old) of both sexes. We assessed insulin-stimulated glucose uptake (ISGU) in musc ...[more]

PMID: 41105193

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Project description:Calorie restriction (CR) enhances longevity and mitigates aging phenotypes in numerous species. Physiological responses to CR are cell-type specific and variable throughout the lifespan; however, the mosaic of molecular changes responsible CR benefits remain unclear, particularly in brain regions susceptible to deterioration throughout aging. Thus, we examined the influence of long-term CR on the CA1 hippocampal region, a key learning and memory brain area that is vulnerable to age-related pathologies, such as Alzheimerâs disease (AD). Through mRNA sequencing and NanoString nCounter analysis, we demonstrate that one year of CR feeding suppresses an age-dependent signature of 882 genes functionally associated with synaptic transmission-related pathways, including calcium signaling, long-term potentiation (LTP), and Creb signaling in wild-type mice. By comparing the influence of CR on hippocampal CA1 region transcriptional profiles at younger- (5 months) and older-adult (15 months) timepoints, we identify conserved upregulation of proteome quality control and calcium buffering genes, including heat shock 70 kDa proteins 1b and 5 (Hspa1b and Hspa5), protein disulfide isomerase family A members 4 and 6 (Pdia4 and Pdia6), and calreticulin (Calr). Expression levels of putative neuroprotective factors, klotho (Kl) and transthyretin (Ttr), are also elevated by CR throughout adulthood, although the global CR-specific expression profiles at young and older timepoints are highly divergent. At a previously unachieved resolution, our results demonstrate conserved activation of neuroprotective gene signatures and broad CR-suppression of age-dependent hippocampal CA1 region expression changes, indicating that CR functionally maintains a more youthful transcriptional state within hippocampal CA1 throughout aging. Hippocampal CA1 region mRNA profiles of younger- (5 months) and older-adult (15 months) mice on calorie-restricted (CR) and normal (AD) diets were generated by deep sequencing using Illumina HiSeq 2500.