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. 2013 Jun 3;8(6):e65118.
doi: 10.1371/journal.pone.0065118. Print 2014.

Heterogeneous effects of calorie restriction on in vivo glucose uptake and insulin signaling of individual rat skeletal muscles

Naveen Sharma  1 , Donel A Sequea, Carlos M Castorena, Edward B Arias, Nathan R Qi, Gregory D Cartee
Affiliations

Heterogeneous effects of calorie restriction on in vivo glucose uptake and insulin signaling of individual rat skeletal muscles

Naveen Sharma et al. PLoS One. .

Abstract

Calorie restriction (CR) (consuming ~60% of ad libitum, AL, intake) improves whole body insulin sensitivity and enhances insulin-stimulated glucose uptake by isolated skeletal muscles. However, little is known about CR-effects on in vivo glucose uptake and insulin signaling in muscle. Accordingly, 9-month-old male AL and CR (initiated when 3-months-old) Fischer 344 x Brown Norway rats were studied using a euglycemic-hyperinsulinemic clamp with plasma insulin elevated to a similar level (~140 µU/ml) in each diet group. Glucose uptake (assessed by infusion of [(14)C]-2-deoxyglucose, 2-DG), phosphorylation of key insulin signaling proteins (insulin receptor, Akt and Akt substrate of 160 kDa, AS160), abundance of GLUT4 and hexokinase proteins, and muscle fiber type composition (myosin heavy chain, MHC, isoform percentages) were determined in four predominantly fast-twitch (epitrochlearis, gastrocnemius, tibialis anterior, plantaris) and two predominantly slow-twitch (soleus, adductor longus) muscles. CR did not result in greater GLUT4 or hexokinase abundance in any of the muscles, and there were no significant diet-related effects on percentages of MHC isoforms. Glucose infusion was greater for CR versus AL rats (P<0.05) concomitant with significantly (P<0.05) elevated 2-DG uptake in 3 of the 4 fast-twitch muscles (epitrochlearis, gastrocnemius, tibialis anterior), without a significant diet-effect on 2-DG uptake by the plantaris or either slow-twitch muscle. Each of the muscles with a CR-related increase in 2-DG uptake was also characterized by significant (P<0.05) increases in phosphorylation of both Akt and AS160. Among the 3 muscles without a CR-related increase in glucose uptake, only the soleus had significant (P<0.05) CR-related increases in Akt and AS160 phosphorylation. The current data revealed that CR leads to greater whole body glucose disposal in part attributable to elevated in vivo insulin-stimulated glucose uptake by fast-twitch muscles. The results also demonstrated that CR does not uniformly enhance either insulin signaling or insulin-stimulated glucose uptake in all muscles in vivo.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Rat body mass (A) and daily food intake (B).
Filled boxes are the AL group and open bars are the CR group. Rats were weighed weekly. Weekly food allotment for the CR group was based on AL group’s food intake for the previous week. When rats were ∼3 mo-old, the food intake of the CR group was reduced to 90% of AL for a week, 75% of AL for the following week, and continued at 60–65% of AL thereafter. *P<0.05 AL versus CR group. Data are means. For clarity, SE bars are not included.
Figure 2
Figure 2. 2-Deoxyglucose (2-DG) uptake in predominantly fast-twitch and predominantly slow-twitch muscles.
EPI, epitrochlearis; GN, gastrocnemius; TA, tibialis anterior; PLN, plantaris; SOL, soleus; ADL, adductor longus. Filled bars are the AL group and open bars are the CR group. *P<0.05, CR versus AL. Data are means ± SE. n = 6–13 rats per treatment group.
Figure 3
Figure 3. Insulin receptor Tyr1162/1163 phosphorylation (pIRTyr1162/1163) in predominantly fast-twitch and predominantly slow-twitch muscles.
EPI, epitrochlearis; GN, gastrocnemius; TA, tibialis anterior; PLN, plantaris; SOL, soleus; ADL, adductor longus. Filled bars are the AL group and open bars are the CR group. Values are normalized to the average value of the AL samples on each blot. Each graph in Figures 3 to 9 is accompanied by representative blots from two muscles from AL and CR rats (the dashed line denotes two independent blots). Data are means ± SE. n = 6–8 rats per treatment group.
Figure 4
Figure 4. Akt Ser473 phosphorylation (pAktSer473) in predominantly fast-twitch and predominantly slow-twitch muscles.
EPI, epitrochlearis; GN, gastrocnemius; TA, tibialis anterior; PLN, plantaris; SOL, soleus; ADL, adductor longus. Filled bars are the AL group and open bars are the CR group. Values are normalized to the average value of the AL samples on each blot. *P<0.05, CR versus AL. Data are means ± SE. n = 6–8 rats per treatment group.
Figure 5
Figure 5. Akt Thr308 phosphorylation (pAktThr308) in predominantly fast-twitch and predominantly slow-twitch muscles.
EPI, epitrochlearis; GN, gastrocnemius; TA, tibialis anterior; PLN, plantaris; SOL, soleus; ADL, adductor longus. Filled bars are the AL group and open bars are the CR group. Values are normalized to the average value of the AL samples on each blot. *P<0.05, CR versus AL. Data are means ± SE. n = 5–8 rats per treatment group.
Figure 6
Figure 6. AS160 Thr642 phosphorylation (pAS160Thr642) in predominantly fast-twitch and predominantly slow-twitch muscles.
EPI, epitrochlearis; GN, gastrocnemius; TA, tibialis anterior; PLN, plantaris; SOL, soleus; ADL, adductor longus. Filled bars are the AL group and open bars are the CR group. Values are normalized to the average value of the AL samples on each blot. *P<0.05, CR versus AL. Data are means ± SE. n = 6–8 rats per treatment group.
Figure 7
Figure 7. AS160 Ser588 phosphorylation (pAS160Ser588) in predominantly fast-twitch and predominantly slow-twitch muscles.
EPI, epitrochlearis; GN, gastrocnemius; TA, tibialis anterior; PLN, plantaris; SOL, soleus; ADL, adductor longus. Filled bars are the AL group and open bars are the CR group. Values are normalized to the average value of the AL samples on each blot. *P<0.05, CR versus AL. Data are means ± SE. n = 6–8 rats per treatment group.
Figure 8
Figure 8. GLUT4 protein abundance in predominantly fast-twitch and predominantly slow-twitch muscles.
EPI, epitrochlearis; GN, gastrocnemius; TA, tibialis anterior; PLN, plantaris; SOL, soleus; ADL, adductor longus. Filled bars are the AL group and open bars are the CR group. Values are normalized to the average value of the AL samples on each blot. *P<0.05, CR versus AL. Data are means ± SE. n = 8–13 rats per treatment group.
Figure 9
Figure 9. Hexokinase protein abundance in predominantly fast-twitch and predominantly slow-twitch muscles.
EPI, epitrochlearis; GN, gastrocnemius; TA, tibialis anterior; PLN, plantaris; SOL, soleus; ADL, adductor longus. Filled bars are the AL group and open bars are the CR group. Values are normalized to the average value of the AL samples on each blot. Data are means ± SE. n = 7–8 rats per treatment group.
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