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Tissue-specific responses of IGF-1/insulin and mTOR signaling in calorie restricted rats.

Sharma N, Castorena CM, Cartee GD - PLoS ONE (2012)

Bottom Line: The most striking and consistent effect of CR was greater pAkt in 3 of the 5 skeletal muscles of CR vs.There were no significant CR effects on the mTOR signaling pathway and no evidence that CR caused a general attenuation of mTOR signaling across the tissues studied.Rather than supporting the premise of a global downregulation of insulin/IGF-1 and/or mTOR signaling in many tissues, the current results revealed clear tissue-specific CR effects for the insulin signaling pathway without CR effects on the mTOR signaling pathway.

View Article: PubMed Central - PubMed

Affiliation: Muscle Biology Laboratory, School of Kinesiology, University of Michigan, Ann Arbor, Michigan, United States of America.

ABSTRACT
Moderate calorie restriction (CR) (∼60% of ad libitum, AL, intake) has been associated with numerous favorable physiological outcomes in many species, and the insulin/IGF-1 and mTOR signaling pathways have each been proposed as potential mediators for many of CR's bioeffects. However, few studies have assessed the widely held idea that CR induces the down-regulation of the insulin/IGF-1 and/or mTOR pathways in multiple tissues. Accordingly, we analyzed the phosphorylation status of 11 key signaling proteins from the insulin/IGF-1 (IR(Tyr1162/1163), IGF-1R(Tyr1135/1136), IRS-1(Ser312), PTEN(Ser380), Akt(Ser473), GSK3α(Ser21), GSK3β(Ser9)) and mTOR (TSC2(Ser939), mTOR(Ser2448), P70S6K(Thr412), RPS6(Ser235/236)) pathways in 11 diverse tissues [liver, kidney, lung, aorta, two brain regions (cortex and cerebellum), and two slow-twitch and three fast-twitch skeletal muscles] from 9-month-old male AL and CR Fischer 344 x Brown Norway rats. The rats were studied under two conditions: with endogenous insulin levels (i.e., AL>CR) and with insulin infused during a hyperinsulinemic-euglycemic clamp so that plasma insulin concentrations were matched between the two diet groups. The most striking and consistent effect of CR was greater pAkt in 3 of the 5 skeletal muscles of CR vs. AL rats. There were no significant CR effects on the mTOR signaling pathway and no evidence that CR caused a general attenuation of mTOR signaling across the tissues studied. Rather than supporting the premise of a global downregulation of insulin/IGF-1 and/or mTOR signaling in many tissues, the current results revealed clear tissue-specific CR effects for the insulin signaling pathway without CR effects on the mTOR signaling pathway.

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Related in: MedlinePlus

Insulin/IGF-1 and mTOR signaling in predominantly fast-twitch muscles.Open bars are the AL-SLN group, gray bars are the CR-SLN group, hatched bars are the AL-INS group, and black bars are the CR-INS group. Values are expressed as phosphorylated-to-total protein ratio. Main effects of Diet, Insulin Infusion (Ins), and Diet×Insulin Infusion Interactions (D×I) from 2-way ANOVA are shown in each panel. *P≤0.000138. Data are means ± SEM. n = 6 rats per diet group and treatment.
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pone-0038835-g002: Insulin/IGF-1 and mTOR signaling in predominantly fast-twitch muscles.Open bars are the AL-SLN group, gray bars are the CR-SLN group, hatched bars are the AL-INS group, and black bars are the CR-INS group. Values are expressed as phosphorylated-to-total protein ratio. Main effects of Diet, Insulin Infusion (Ins), and Diet×Insulin Infusion Interactions (D×I) from 2-way ANOVA are shown in each panel. *P≤0.000138. Data are means ± SEM. n = 6 rats per diet group and treatment.

Mentions: To eliminate false positives due to multiple comparisons in the protein phosphorylation data, we used a high stringency statistical threshold (P≤0.000138). The most consistent effects were found for insulin signaling in skeletal muscle. For pAktSer473, there was a significant (P≤0.000138) main effect of diet (CR>AL) in the EPI, TA, and PLN, and a significant (P≤0.000138) main effect of insulin infusion (INS>SLN) in the SOL, TA, and PLN (Figs. 1 & 2). There was also a significant (P≤0.000138) main effect of insulin infusion (INS>SLN) in the SOL for pIRTyr1135/1136 (Fig. 1). There were no significant effects of diet or insulin infusion in any of the other tissues (Figs. 3, 4, 5).


Tissue-specific responses of IGF-1/insulin and mTOR signaling in calorie restricted rats.

Sharma N, Castorena CM, Cartee GD - PLoS ONE (2012)

Insulin/IGF-1 and mTOR signaling in predominantly fast-twitch muscles.Open bars are the AL-SLN group, gray bars are the CR-SLN group, hatched bars are the AL-INS group, and black bars are the CR-INS group. Values are expressed as phosphorylated-to-total protein ratio. Main effects of Diet, Insulin Infusion (Ins), and Diet×Insulin Infusion Interactions (D×I) from 2-way ANOVA are shown in each panel. *P≤0.000138. Data are means ± SEM. n = 6 rats per diet group and treatment.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3368930&req=5

pone-0038835-g002: Insulin/IGF-1 and mTOR signaling in predominantly fast-twitch muscles.Open bars are the AL-SLN group, gray bars are the CR-SLN group, hatched bars are the AL-INS group, and black bars are the CR-INS group. Values are expressed as phosphorylated-to-total protein ratio. Main effects of Diet, Insulin Infusion (Ins), and Diet×Insulin Infusion Interactions (D×I) from 2-way ANOVA are shown in each panel. *P≤0.000138. Data are means ± SEM. n = 6 rats per diet group and treatment.
Mentions: To eliminate false positives due to multiple comparisons in the protein phosphorylation data, we used a high stringency statistical threshold (P≤0.000138). The most consistent effects were found for insulin signaling in skeletal muscle. For pAktSer473, there was a significant (P≤0.000138) main effect of diet (CR>AL) in the EPI, TA, and PLN, and a significant (P≤0.000138) main effect of insulin infusion (INS>SLN) in the SOL, TA, and PLN (Figs. 1 & 2). There was also a significant (P≤0.000138) main effect of insulin infusion (INS>SLN) in the SOL for pIRTyr1135/1136 (Fig. 1). There were no significant effects of diet or insulin infusion in any of the other tissues (Figs. 3, 4, 5).

Bottom Line: The most striking and consistent effect of CR was greater pAkt in 3 of the 5 skeletal muscles of CR vs.There were no significant CR effects on the mTOR signaling pathway and no evidence that CR caused a general attenuation of mTOR signaling across the tissues studied.Rather than supporting the premise of a global downregulation of insulin/IGF-1 and/or mTOR signaling in many tissues, the current results revealed clear tissue-specific CR effects for the insulin signaling pathway without CR effects on the mTOR signaling pathway.

View Article: PubMed Central - PubMed

Affiliation: Muscle Biology Laboratory, School of Kinesiology, University of Michigan, Ann Arbor, Michigan, United States of America.

ABSTRACT
Moderate calorie restriction (CR) (∼60% of ad libitum, AL, intake) has been associated with numerous favorable physiological outcomes in many species, and the insulin/IGF-1 and mTOR signaling pathways have each been proposed as potential mediators for many of CR's bioeffects. However, few studies have assessed the widely held idea that CR induces the down-regulation of the insulin/IGF-1 and/or mTOR pathways in multiple tissues. Accordingly, we analyzed the phosphorylation status of 11 key signaling proteins from the insulin/IGF-1 (IR(Tyr1162/1163), IGF-1R(Tyr1135/1136), IRS-1(Ser312), PTEN(Ser380), Akt(Ser473), GSK3α(Ser21), GSK3β(Ser9)) and mTOR (TSC2(Ser939), mTOR(Ser2448), P70S6K(Thr412), RPS6(Ser235/236)) pathways in 11 diverse tissues [liver, kidney, lung, aorta, two brain regions (cortex and cerebellum), and two slow-twitch and three fast-twitch skeletal muscles] from 9-month-old male AL and CR Fischer 344 x Brown Norway rats. The rats were studied under two conditions: with endogenous insulin levels (i.e., AL>CR) and with insulin infused during a hyperinsulinemic-euglycemic clamp so that plasma insulin concentrations were matched between the two diet groups. The most striking and consistent effect of CR was greater pAkt in 3 of the 5 skeletal muscles of CR vs. AL rats. There were no significant CR effects on the mTOR signaling pathway and no evidence that CR caused a general attenuation of mTOR signaling across the tissues studied. Rather than supporting the premise of a global downregulation of insulin/IGF-1 and/or mTOR signaling in many tissues, the current results revealed clear tissue-specific CR effects for the insulin signaling pathway without CR effects on the mTOR signaling pathway.

Show MeSH
Related in: MedlinePlus