Pharmacological Vasodilation Improves Insulin-Stimulated Muscle Protein Anabolism but Not Glucose Utilization in Older Adults

Sealy Center on Aging, University of Texas Medical Branch, Galveston, Texas, USA.
Diabetes (Impact Factor: 8.1). 11/2010; 59(11):2764-71. DOI: 10.2337/db10-0415
Source: PubMed


Skeletal muscle protein metabolism is resistant to the anabolic action of insulin in healthy, nondiabetic older adults. This defect is associated with impaired insulin-induced vasodilation and mTORC1 signaling. We hypothesized that, in older subjects, pharmacological restoration of insulin-induced capillary recruitment would improve the response of muscle protein synthesis and anabolism to insulin.
Twelve healthy, nondiabetic older subjects (71 ± 2 years) were randomized to two groups. Subjects were studied at baseline and during local infusion in one leg of insulin alone (Control) or insulin plus sodium nitroprusside (SNP) at variable rate to double leg blood flow. We measured leg blood flow by dye dilution; muscle microvascular perfusion with contrast enhanced ultrasound; Akt/mTORC1 signaling by Western blotting; and muscle protein synthesis, amino acid, and glucose kinetics using stable isotope methodologies.
There were no baseline differences between groups. Blood flow, muscle perfusion, phenylalanine delivery to the leg, and intracellular availability of phenylalanine increased significantly (P < 0.05) in SNP only. Akt phosphorylation increased in both groups but increased more in SNP (P < 0.05). Muscle protein synthesis and net balance (nmol · min(-1) · 100 ml · leg(-1)) increased significantly (P < 0.05) in SNP (synthesis, 43 ± 6 to 129 ± 25; net balance, -16 ± 3 to 26 ± 12) but not in Control (synthesis, 41 ± 10 to 53 ± 8; net balance, -17 ± 3 to -2 ± 3).
Pharmacological enhancement of muscle perfusion and amino acid availability during hyperinsulinemia improves the muscle protein anabolic effect of insulin in older adults.

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Available from: Melinda Sheffield-Moore, Aug 17, 2014
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    • "Evidence indicates that reduced endothelial nitric oxide production contributes to the agerelated increase in AP (Cecelja et al., 2012). Recently, endothelial dysfunction has been linked to sarcopenia due to reduced muscle perfusion (Timmerman et al., 2010). Although a relationship between leg sarcopenia and increased resting radial or aortic AIx has been reported in non-obese older adults (Ohara et al., 2014; Snijder et al., 2004), this relationship is not observed when very old adults are examined (71 ± 7 years) (Lee et al., 2014). "
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    ABSTRACT: Wave reflection (augmentation pressure [AP] and index [AIx]) is greater in older women than men. Resting AP is a better wave reflection index than AIx in older adults. The negative relationship between wave reflection and lean mass (LM) has been inconsistent. We investigated the impact of age and LM on aortic hemodynamic responses to metaboreflex activation in postmenopausal women. Postmenopausal women, younger and older (n=20 per group) than 60years, performed 2-min isometric handgrip at 30% of maximal force followed by 3-min post-exercise muscle ischemia (PEMI). We measured carotid-femoral pulse wave velocity (cfPWV) and femoral-ankle PWV (faPWV) at rest, and aortic systolic blood pressure (aSBP), pulse pressure (aPP), AP, AIx, and AIx-adjusted for heart rate (AIx@75) at rest and during PEMI using tonometry. Arm and leg LM were measured by DEXA. Resting cfPWV, aSBP, and aPP were higher, while AIx@75 and leg LM were lower in older than younger women. aSBP and aPP increased similarly during PEMI in both groups. Increases in AP (P<0.05), AIx (P<0.05), and AIx@75 (P<0.01) during PEMI were greater in older than younger women. From these responses, only AP during PEMI was correlated (P<0.05) positively with aSBP and aPP responses, and negatively with leg LM. Resting faPWV, but not cfPWV, was correlated (P<0.01) with AP, aSBP, and aPP during PEMI. Therefore, PEMI induces greater wave reflection responses in older than younger postmenopausal women. Our findings suggest that the increased AP response to PEMI is related to leg arterial stiffness and muscle loss in older women. Copyright © 2015. Published by Elsevier Inc.
    Experimental gerontology 07/2015; 70. DOI:10.1016/j.exger.2015.07.010 · 3.49 Impact Factor
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    • "Fujita et al. (2006) reported that muscle protein synthesis correlates with muscle blood flow (r = 0.79, P <0.0001). Timmerman et al. (2010) found that muscle protein synthesis increases in response to stimulation of muscle blood flow. Cold water immersion reduces blood flow to muscle (Gregson et al., 2011; Mawhinney et al., 2013) and the limbs (Vaile et al., 2010). "
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    ABSTRACT: We investigated functional, morphological and molecular adaptations to strength training exercise and cold water immersion (CWI) through two separate studies. In one study, 21 physically active men strength trained for 12 weeks (2 d⋅wk(-1) ), with either 10 min of CWI or active recovery (ACT) after each training session. Strength and muscle mass increased more in the ACT group than in the CWI group (P<0.05). Isokinetic work (19%), type II muscle fibre cross-sectional area (17%) and the number of myonuclei per fibre (26%) increased in the ACT group (all P<0.05) but not the CWI group. In another study, nine active men performed a bout of single-leg strength exercises on separate days, followed by CWI or ACT. Muscle biopsies were collected before and 2, 24 and 48 h after exercise. The number of satellite cells expressing neural cell adhesion molecule (NCAM) (10-30%) and paired box protein (Pax7)(20-50%) increased 24-48 h after exercise with ACT. The number of NCAM(+) satellitecells increased 48 h after exercise with CWI. NCAM(+) - and Pax7(+) -positivesatellite cell numbers were greater after ACT than after CWI (P<0.05). Phosphorylation of p70S6 kinase(Thr421/Ser424) increased after exercise in both conditions but was greater after ACT (P<0.05). These data suggest that CWI attenuates the acute changes in satellite cell numbers and activity of kinases that regulate muscle hypertrophy, which may translate to smaller long-term training gains in muscle strength and hypertrophy. The use of CWI as a regular post-exercise recovery strategy should be reconsidered. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    The Journal of Physiology 07/2015; 593(18). DOI:10.1113/JP270570 · 5.04 Impact Factor
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    • "The decreased insulin sensitivity observed with ageing is associated with blunted endothelial-dependent vasodilation [21]. It has therefore been proposed that senescent muscle is more resistant to the stimulating effect of post-prandial insulin levels on muscle perfusion and, as such, amino acid delivery to the muscle [22,23]. In agreement, work by Fujita et al.[11] has shown that local insulin administration in older adults increases muscle protein synthesis rates. "
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    ABSTRACT: Background A blunted muscle protein synthetic response to protein ingestion may contribute to the age related loss of muscle tissue. We hypothesized that the greater endogenous insulin release following co-ingestion of carbohydrate facilitates post-prandial muscle protein accretion after ingesting a meal-like bolus of protein in older males. Methods Twenty-four healthy older men (75±1 y) were randomly assigned to ingest 20 g intrinsically L-[1-13C] phenylalanine-labeled casein protein with (PRO-CHO) or without (PRO) 40 g carbohydrate. Ingestion of specifically produced intrinsically L-[1-13C] phenylalanine labeled protein allowed us to assess post-prandial incorporation of dietary protein derived amino acids into muscle protein. Blood samples were collected at regular intervals, with muscle biopsies being obtained prior to and 2 and 6 h after protein ingestion. Results Plasma glucose and insulin concentrations showed a greater increase in PRO-CHO compared with PRO (P<0.001). Muscle protein-bound L-[1-13C] phenylalanine enrichments tended to increase to a greater extent in PRO-CHO compared with PRO during the first 2 h after protein ingestion (0.0072±0.0013 vs 0.0046±0.010 MPE, respectively; P=0.13). However, 6 h after protein ingestion, differences in muscle protein-bound L-[1-13C] phenylalanine enrichments were no longer observed between experiments (0.0213±0.0024 vs 0.0185±0.0010 MPE, respectively; P=0.30). Conclusions This study shows that carbohydrate ingestion may accelerate, but does not further augment post-prandial incorporation of dietary protein derived amino acids into muscle protein in healthy elderly men.
    Nutrition & Metabolism 01/2013; 10(1):15. DOI:10.1186/1743-7075-10-15 · 3.26 Impact Factor
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