The contributory role of vascular health in age-related anabolic resistance.

Sarcopenia, or the age-related loss of skeletal muscle mass and function, is an increasingly prevalent condition that contributes to reduced quality of life, morbidity, and mortality in older adults. Older adults display blunted anabolic responses to otherwise anabolic stimuli-a phenomenon that has been termed anabolic resistance (AR)-which is likely a casual factor in sarcopenia development. AR is multifaceted, but historically much of the mechanistic focus has been on signalling impairments, and less focus has been placed on the role of the vasculature in postprandial protein kinetics. The vascular endothelium plays an indispensable role in regulating vascular tone and blood flow, and age-related impairments in vascular health may impede nutrient-stimulated vasodilation and subsequently the ability to deliver nutrients (e.g. amino acids) to skeletal muscle. Although the majority of data has been obtained studying younger adults, the relatively limited data on the effect of blood flow on protein kinetics in older adults suggest that vasodilatory function, especially of the microvasculature, strongly influences the muscle protein synthetic response to amino acid feedings. In this narrative review, we examine evidence of AR in older adults following amino acid and mixed meal consumption, examine the evidence linking vascular dysfunction and insulin resistance to age-related AR, review the influence of nitric oxide and endothelin-1 on age-related vascular dysfunction as it relates to AR, briefly review the potential causal role of arterial stiffness in promoting skeletal muscle microvascular dysfunction and AR, and provide a brief overview and future considerations for research examining age-related AR.

Perioperative amino acid infusion reestablishes muscle net balance during total hip arthroplasty.

Surgery and anesthesia induce a catabolic response that leads to skeletal muscle protein loss. Previous investigations have observed positive effects of perioperative nutrition. Furthermore, the benefits of exogenous amino acids on muscle protein kinetics are well established. However, no investigation has focused on muscle protein kinetics with and without perioperative amino acid infusion. Thus, we aimed to assess the effect of perioperative amino acid (AA) infusion on muscle protein balance in individuals undergoing elective total hip arthroplasty (THA). Elective THA patients were randomized to undergo a metabolic study prior to surgery (n = 5; control [CON]), intraoperative AA infusion (n = 9), or no AA (n = 13; standard of care [SC]). The CON group was studied prior to surgery to provide nonoperative/non-anesthesia muscle protein kinetic reference values. The bolus infusion method with 13 C6 -phenylalanine injected at time 0, and [15 N]-phenylalanine 30 min later was used to calculate muscle protein synthesis (MPS), protein breakdown (MPB), and net balance (MPS-MPB). Perioperative AA significantly improved muscle net balance as compared to SC (-0.005 ± 0.018%/h vs. -0.052 ± 0.011%/h) but not CON (0.003 ± 0.013%/h). The AA infusion significantly increased muscle net balance via a significant increase in MPS (AA = 0.062 ± 0.007%/h; SC = 0.037 ± 0.004%/h; CON = 0.072% ± 0.005%/h), and a nonsignificant attenuation of MPB (AA = 0.067 ± 0.012%/h; SC = 0.089 ± 0.014%/h; CON = 0.075 ± 0.011%/h). Our data support the use of perioperative AA infusion during elective THA as pragmatic strategy to offset the loss of surgically induced skeletal muscle protein.

The effects of concurrent training order on body composition and serum concentrations of follistatin, myostatin and GDF11 in sarcopenic elderly men.

BACKGROUND: Due to the important role of follistatin (FLST), myostatin (MSTN) and growth differentiation factor 11 (GDF11) in muscle mass regulation; alterations in the FLST to MSTN ratio (F:M) may result in muscle mass changes in response to different concurrent training (CT) order. This study investigated the influence of 8 weeks of CT order on body composition and serum concentrations of FLST, MSTN, their ratio (F:M) and GDF11 in sarcopenic elderly men. METHODS: Thirty sarcopenic elderly men (age = 64.3 ± 3.5 years) were randomly assigned into one of three groups, endurance followed by resistance training (E + R; n = 10), resistance followed by endurance training (R + E; n = 10) or control (C; n = 10). Serum concentrations of muscle regulatory markers, body composition, maximum rate of oxygen consumption (VO2max), and upper and lower body strength were evaluated at baseline and after 8 weeks. The training protocol consisted of three training sessions per week for eight weeks. RESULTS: There were significant group-by-time interactions (P < 0.05) for FLST, MSTN, GDF11 and F:M ratio. FLST (E + R = 187 pg/mL and R + E = 292 pg/mL) and F:M ratio (E + R = 0.20 and R + E = 0.27) significantly increased (P < 0.05) while MSTN (E + R = -308 pg/mL and R + E = -294 pg/mL) and GDF11 (E + R = -12 pg/mL and R + E = -10 pg/mL) significantly decreased (P < 0.05) following eight weeks in the E + R and R + E compared to no changes in the C group. In addition, there were significant group x time interactions (P < 0.01) for weight, BMI, body fat percentage (BFP), skeletal muscle mass (SMM), VO2max, upper body strength, and lower body strength. BFP (E + R = -1.5% and R + E = -2%) significantly decreased (P < 0.01) while weight (E + R = 2.4 kg and R + E = 1.1 kg), BMI (E + R = 0.8 kg/m2 and R + E = 0.3 kg/m2), SMM (E + R = 0.7 kg and R + E = 0.5 kg), VO2max (E + R = 2.0 mL/kg/min and R + E = 1.8 mL/kg/min), upper body strength (E + R = 6.9 kg and R + E = 2.3 kg), and lower body strength (E + R = 9.8 kg and R + E = 4.4 kg) significantly increased (P < 0.01) in the E + R and R + E compared to no changes in the C group. CONCLUSIONS: CT increases the F:M ratio and FLST as well as reducing MSTN and GDF11 in sarcopenic elderly men. Additionally, CT improved weight, body composition, muscle mass, function, and aerobic fitness. Notably, these results after CT were achieved irrespective of endurance and resistance exercise order in this population.

Resistance Exercise Selectively Mobilizes Monocyte Subsets: Role of Polyphenols.

PURPOSE: To examine the impact of polyphenol supplementation on the recruitment, mobilization, and activation of monocyte subsets after resistance exercise. METHODS: Thirty-eight recreationally active males (22.1 ± 3.1 yr; 173.9 ± 7.9 cm; 77.8 ± 14.5 kg) were assigned to 28 d of polyphenol blend (PPB) supplementation, placebo (PL), or control (CON). Blood samples were obtained before (PRE) postresistance exercise, immediately (IP) postresistance exercise, 1 h (1H) postresistance exercise, 5 h (5H) postresistance exercise, 24 h (24H) postresistance exercise, and 48 h (48H) postresistance exercise (PPB/PL) or rest (CON). Fine-needle biopsies were obtained from the vastus lateralis at PRE, 1H, 5H, and 48H. Circulating concentrations of macrophage chemoattractant protein-1 (MCP-1) and fractalkine, as well as intramuscular MCP-1 were analyzed via multiplex assay. Changes in the proportions and expression of CD11b on monocyte subsets were assessed via flow cytometry. RESULTS: Circulating MCP-1 increased in PPB and PL at IP with further increases at 5H. Intramuscular MCP-1 was increased at 1H, 5H, and 48H in all groups. Classical monocyte proportions were reduced in PPB and PL at IP, and increased at 1H. Nonclassical monocytes were increased in PPB and PL at IP, whereas intermediate monocytes were increased at IP, and reduced at 1H. Intermediate monocytes were increased in PPB at 24H and 48H. CD11b expression was reduced on PPB compared with PL and CON at PRE on intermediate and nonclassical monocytes. CONCLUSIONS: Resistance exercise may elicit selective mobilization of intermediate monocytes at 24H and 48H, which may be mediated by tissue damage. Additionally, polyphenol supplementation may suppress CD11b expression on monocyte subsets at rest.

Polyphenol supplementation alters intramuscular apoptotic signaling following acute resistance exercise.

The purpose of this study was to examine the effects of 28-days of supplementation with an aqueous proprietary polyphenol blend (PPB) sourced from Camellia sinensis on intramuscular apoptotic signaling following an acute lower-body resistance exercise protocol and subsequent recovery. Untrained males (n = 38, 21.8 ± 2.7 years, 173.4 ± 7.9 cm, 77.6 ± 14.6 kg) were randomized to PPB (n = 14), placebo (PL; n = 14) or control (CON; n = 10). Participants completed a lower-body resistance exercise protocol comprised of the squat, leg press, and leg extension exercises. Skeletal muscle microbiopsies were obtained from the vastus lateralis preexercise (PRE), 1-h (1HR), 5-h (5HR), and 48-h (48HR) post-resistance exercise. Apoptotic signaling pathways were quantified using multiplex signaling assay kits to quantify total proteins (Caspase 3, 8, 9) and markers of phosphorylation status (JNK, FADD, p53, BAD, Bcl-2). Changes in markers of muscle damage and intramuscular signaling were analyzed via separate repeated measures analysis of variance (ANOVA). Change in Bcl-2 phosphorylation at 1H was significantly greater in PL compared to CON (P = 0.001). BAD phosphorylation was significantly elevated at 5H in PL compared to PPB (P = 0.015) and CON (P = 0.006). The change in JNK phosphorylation was significantly greater in PPB (P = 0.009), and PL (P = 0.017) compared to CON at 1H, while the change for PL was elevated compared to CON at 5H (P = 0.002). A main effect was observed (P < 0.05) at 1H, 5H, and 48H for p53 and Caspase 8, with Caspase 3 and Caspase 9 elevated at 48H. These data indicate that chronic supplementation with PPB alters apoptotic signaling in skeletal muscle following acute muscle-damaging resistance exercise.

Impact of Polyphenol Supplementation on Acute and Chronic Response to Resistance Training.

Beyer, KS, Stout, JR, Fukuda, DH, Jajtner, AR, Townsend, JR, Church, DD, Wang, R, Riffe, JJ, Muddle, TWD, Herrlinger, KA, and Hoffman, JR. Impact of polyphenol supplementation on acute and chronic response to resistance training. J Strength Cond Res 31(11): 2945-2954, 2017-This study investigated the effect of a proprietary polyphenol blend (PPB) on acute and chronic adaptations to resistance exercise. Forty untrained men were assigned to control, PPB, or placebo. Participants in PPB or placebo groups completed a 4-week supplementation period (phase I), an acute high-volume exercise bout (phase II), and a 6-week resistance training program (phase III); whereas control completed only testing during phase II. Blood draws were completed during phases I and II. Maximal strength in squat, leg press, and leg extension were assessed before and after phase III. The exercise protocol during phase II consisted of squat, leg press, and leg extension exercises using 70% of the participant's strength. The resistance training program consisted of full-body exercises performed 3 d·wk. After phase I, PPB (1.56 ± 0.48 mM) had greater total antioxidant capacity than placebo (1.00 ± 0.90 mM). Changes in strength from phase III were similar between PPB and placebo. Polyphenol blend supplementation may be an effective strategy to increase antioxidant capacity without limiting strength gains from training.

Tumor necrosis factor-alpha and soluble TNF-alpha receptor responses in young vs. middle-aged males following eccentric exercise.

BACKGROUND: Tumor necrosis factor-alpha (TNF-α) has been shown to be implicated in both muscle regeneration and muscle wasting. However, it remains unclear whether TNF-α is responsible for the age-related losses in muscle size and function. Also, due to the high clearance rate of TNF-α from circulation, analyzing the circulating levels of soluble TNF-α receptors 1 and 2 (STNFR1 and STNFR2) may provide a better indication of inflammatory events. The aim of this study was to examine changes in circulating concentrations of TNF-α, STNFR1, and STNFR2 following acute eccentric exercise in young (YA) and middle-aged (MA) men. METHODS AND MATERIALS: Nine YA (N=9, 21.8±2.2y, 179.5±4.9cm, 91.2±12.2kg, 21.8±4.3% body fat) and ten MA (N=10, 47.0±4.4y, 176.8±7.6cm; 96.0±21.5kg, 25.4±5.3% body fat) men completed an acute muscle damaging protocol (MDP). Blood samples were obtained at baseline (BL), immediately (IP), 30-minute (30P), 60-minute (60P), 120-minute (120P), 24-hour (24H), and 48-hour (48H) post-MDP. Lower body performance was assessed via isokinetic dynamometer at BL, IP, 120P, 24H, and 48H. RESULTS: YA displayed higher values of peak torque (p=0.023) and mean torque (p=0.036) at BL. No significant group differences were observed for markers of muscle damage or TNF-α. Plasma concentrations of TNF-α were unchanged following MDP. STNFR1 concentrations were significantly higher in the YA group compared to MA (p=0.036). Significant time effects were observed for STNFR1 (p<0.001) and STNFR2 (p=0.001). With both groups combined, serum STNFR1 was decreased at 30P (p=0.001), while STNFR2 was decreased at 30P (p=0.008), 60P (p=0.003), and 120P (p=0.002) relative to BL. CONCLUSIONS: The pro-inflammatory response to muscle damage does not appear to decline at middle age when individuals are recreationally trained. However, young men showed significantly higher serum STNFR1 concentrations than middle age men. This may suggest that natural inhibitors of TNF-α decline as early as middle age.

Comparison of Two ß-Alanine Dosing Protocols on Muscle Carnosine Elevations.

OBJECTIVE: ß-alanine (BA) is a nonproteogenic amino acid that combines with histidine to form carnosine. The amount taken orally in individual doses, however, is limited due to symptoms of paresthesia that are associated with higher doses. The use of a sustained-release formulation has been reported to reduce the symptoms of paresthesia, suggesting that a greater daily dose may be possible. The purpose of the present study was to determine whether increasing the daily dose of BA can result in a similar increase in muscle carnosine in a reduced time. METHODS: Eighteen men and twelve women were randomized into either a placebo (PLC), 6-g BA (6G), or 12-g BA (12G) groups. PLC and 6G were supplemented for 4 weeks, while 12G was supplemented for 2 weeks. A resting blood draw and muscle biopsy were obtained prior to (PRE) and following (POST) supplementation. Plasma and muscle metabolites were measured by high-performance liquid chromatography. The loss in peak torque (ΔPT) was calculated from maximal isometric contractions before and after 250 isokinetic kicks at 180°·sec-1 PRE and POST. RESULTS: Both 12G (p = 0.026) and 6G (p = 0.004) increased muscle carnosine compared to PLC. Plasma histidine was decreased from PRE to POST in 12G compared to PLC (p = 0.002) and 6G (p = 0.001), but no group x time interaction (p = 0.662) was observed for muscle histidine. No differences were observed for any hematological measure (e.g., complete blood counts) or in symptoms of paresthesia among the groups. Although no interaction was noted in ΔPT, a trend (p = 0.073) was observed. CONCLUSION: Results of this investigation indicate that a BA supplementation protocol of 12 g/d-1, using a sustained-release formulation, can accelerate the increase in carnosine content in skeletal muscle while attenuating paresthesia.

Post-resistance exercise ingestion of milk protein attenuates plasma TNFα and TNFr1 expression on monocyte subpopulations.

Attenuating TNFα/TNFr1 signaling in monocytes has been proposed as a means of mitigating inflammation. The purpose of this study was to examine the effects of a milk protein supplement on TNFα and monocyte TNFr1 expression. Ten resistance-trained men (24.7 ± 3.4 years; 90.1 ± 11.3 kg; 176.0 ± 4.9 cm) ingested supplement (SUPP) or placebo (PL) immediately post-exercise in a randomized, cross-over design. Blood samples were obtained at baseline (BL), immediately (IP), 30-min (30P), 1-h (1H), 2-h (2H), and 5-h (5H) post-exercise to assess plasma concentrations of myoglobin; tumor necrosis factor-alpha (TNFα); and expression of tumor necrosis factor receptor 1 (TNFr1) on classical, intermediate, and non-classical monocytes. Magnitude-based inferences were used to provide inferences on the true effects of SUPP compared to PL. Plasma TNFα concentrations were "likely attenuated" (91.6% likelihood effect) from BL to 30P in the SUPP group compared with PL (d = 0.87; mean effect: 2.3 ± 2.4 pg mL-1). TNFr1 expressions on classical (75.9% likelihood effect) and intermediate (93.0% likelihood effect) monocytes were "likely attenuated" from BL to 2H in the SUPP group compared with PL (d = 0.67; mean effect: 510 ± 670 RFU, and d = 1.05; mean effect: 2500 ± 2300 RFU, respectively). TNFr1 expression on non-classical monocytes was "likely attenuated" (77.6% likelihood effect) from BL to 1H in the SUPP group compared with PL (d = 0.69; mean effect: 330 ± 430 RFU). Ingestion of a milk protein supplement immediately post-exercise appears to attenuate both plasma TNFα concentrations and TNFr1 expression on monocyte subpopulations in resistance-trained men.

Comparison of the recovery response from high-intensity and high-volume resistance exercise in trained men.

PURPOSE: The purpose of this study was to compare the physiological responses of a high-volume (HV; 8 sets of 10 repetitions) versus high-intensity (HI; 8 sets of 3 repetitions) exercise protocol in resistance-trained men. METHODS: Twelve men (24.5 ± 4.2 years; 82.3 ± 8.4 kg; 175.2 ± 5.5 cm) with 6.3 ± 3.4 years of resistance training experience performed each protocol in a counterbalanced, randomized order. Performance [counter movement jump peak power (CMJP), isokinetic (ISOK) and isometric leg extension (MVIC), isometric mid-thigh pull (IMTP), and isometric squat (ISQ)] and muscle morphological [cross-sectional area (CSA) of vastus lateralis] assessments were performed at baseline (BL), 30-min (P-30 min), 24-h (P-24 h), 48-h (P-48 h), and 72-h (P-72 h) post-exercise for each testing session. In addition, endocrine (testosterone and cortisol), inflammatory [interleukin-6 (IL-6) and C-reactive protein (CRP)], and markers of muscle damage [creatine kinase (CK), lactate dehydrogenase (LDH), and myoglobin (Mb)] were assessed at the same time points. RESULTS: Significantly greater reductions in CMJP (p < 0.001), and peak torque during both ISOK (p = 0.003) and MVIC (p = 0.008) at P-30 min were detected in HV compared to HI protocol. MVIC was still impaired at P-72 h following the HV protocol, while no differences were noted following HI. Markers of muscle damage (LDH, CK, and Mb) were significantly elevated following both HV and HI (p < 0.05), while cortisol and IL-6 concentrations were significantly elevated at P-30 min following HV only (p < 0.001 and p < 0.05, respectively). CONCLUSIONS: Results indicate that high-volume resistance exercise results in greater performance deficits, and a greater extent of muscle damage, than a bout of high-intensity resistance exercise.

ß-Hydroxy-ß-methylbutyrate attenuates cytokine response during sustained military training.

This study tested the hypothesis that of 23 days of ß-hydroxy-ß-methylbutyrate (HMB) supplementation can maintain muscle mass and attenuate the immune and inflammatory response in combat soldiers during highly intense military training. Soldiers were randomly assigned to either a HMB (n = 6) or placebo (PL; n = 7) group and provided with 3 g · day(-1) of either HMB or PL. During the final week of supplementation soldiers participated in extreme physical training, which included night navigation of 6-8 hours across difficult terrain carrying heavy loads combined with sleep deprivation (3.8 ± 3.0 h per night). Blood draws were performed prior to and following the supplementation period. Magnetic resonance imaging, which included diffusion tensor imaging sequence, was used for muscle fiber tracking analysis. Data was analyzed using a two-way mixed factorial analysis of variance. Magnitude-based inferences were used to provide inferences on the true effects that HMB may have had on the dependent variables compared to PL, calculated from 90% confidence intervals. Changes in tumor necrosis factor-α for HMB (-3.9 ± 8.2 pg · mL(-1)) were significantly lower (P = .043) compared to the change in PL (+4.0 ± 3.7 pg · mL(-1)). HMB ingestion was also very likely (92%-95% Likelihood) to lower granulocyte colony-stimulating factor and interleukin 10 compared to PL. In addition, HMB supplementation was likely (78%-87% likelihood) to reduce interferon-γ, interleukin 8, CX3CL1, and increase muscle volume for the adductor magnus (77% likelihood) compared to PL. In summary, the results of this study provides evidence that HMB supplementation may attenuate the inflammatory response to high intense military training, and maintain muscle quality.

Monocyte Recruitment after High-Intensity and High-Volume Resistance Exercise.

UNLABELLED: The innate immune response is generally considered to have an important role in tissue remodeling after resistance exercise. PURPOSE: The purpose of this study was to compare changes in markers of monocyte recruitment after an acute bout of high-intensity (HVY) versus high-volume (VOL) lower-body resistance exercise. METHODS: Ten resistance-trained men (24.7 ± 3.4 yr, 90.1 ± 11.3 kg, 176.0 ± 4.9 cm) performed each protocol in a randomized, counterbalanced order. Blood samples were collected at baseline, immediately (IP), 30 min (30P), 1 h (1H), 2 h (2H), and 5 h (5H) postexercise. Plasma concentrations of monocyte chemoattractant protein 1 (MCP-1), tumor necrosis factor alpha (TNF-α), myoglobin, and cortisol were measured via assay. Tumor necrosis factor receptor 1 (TNFr1), macrophage-1 antigen (cluster of differentiation 11b [CD11b]), and C-C chemokine receptor 2 (CCR2) expression levels were measured using flow cytometry. TNFr1 and CD11b were assessed on CD14CD16 monocytes, whereas CCR2 was assessed on CD14 monocytes. RESULTS: Plasma myoglobin concentrations were significantly greater after HVY compared with VOL (P < 0.001). Changes in plasma TNF-α, MCP-1, and expression levels of CCR2 and CD11b were similar between HVY and VOL. When collapsed across groups, TNF-α was significantly increased at IP, 30P, 1H, and 2H (P values < 0.05), whereas MCP-1 was significantly elevated at all postexercise time points (P values < 0.05). CCR2 expression on CD14 monocytes was significantly lower at IP, 1H, 2H, and 5H (P values < 0.05). CD11b expression on CD14 CD16 was significantly greater at IP (P < 0.014) and 1H (P = 0.009). TNFr1 expression did not differ from baseline at any time point. Plasma cortisol concentrations did not seem to be related to receptor expression. CONCLUSIONS: Results indicate that both HVY and VOL protocols stimulate a robust proinflammatory response. However, no differences were noted between resistance exercise training paradigms.

The effect of polyphenols on cytokine and granulocyte response to resistance exercise.

This study examined the effect of resistance exercise on the production, recruitment, percentage, and adhesion characteristics of granulocytes with and without polyphenol (PPB) supplementation. Thirty-eight untrained men were randomized into three groups: PPB (n = 13, 21.8 ± 2.5 years, 171.2 ± 5.5 cm, 71.2 ± 8.2 kg), placebo (PL; n = 15, 21.6 ± 2.5 years, 176.5 ± 4.9 cm, 84.0 ± 15.7 kg), or control (CON; n = 10, 23.3 ± 4.3 years, 173.7 ± 12.6 cm, 77.3 ± 16.3 kg). Blood samples were obtained pre (PRE), immediately (IP), 1 h (1H), 5 h (5H), 24 h (24H), 48 h (48H), and 96 h (96H) postresistance exercise (PPB/PL) or rest (CON). Fine-needle biopsies were obtained from the vastus lateralis at PRE, 1H, 5H, and 48H. Plasma concentrations and intramuscular content of interleukin-8 (IL-8), granulocyte (G-CSF), and granulocyte-macrophage colony stimulating factor (GM-CSF) were analyzed via multiplex assays. Changes in relative number of circulating granulocytes and adhesion receptor (CD11b) were assessed using flow cytometry. Intramuscular IL-8 was significantly elevated at 1H, 5H, and 48H (P < 0.001). Area under the curve analysis indicated a greater intramuscular IL-8 content in PL than PPB (P = 0.011). Across groups, circulating G-CSF was elevated from PRE at IP (P < 0.001), 1H (P = 0.011), and 5H (P = 0.025), while GM-CSF was elevated at IP (P < 0.001) and 1H (P = 0.007). Relative number of granulocytes was elevated at 1H (P < 0.001), 5H (P < 0.001), and 24H (P = 0.005, P = 0.006) in PPB and PL, respectively. Across groups, granulocyte CD11b expression was upregulated from PRE to IP (P < 0.001) and 1H (P = 0.015). Results indicated an increase in circulating CD11b on granulocytes, and IL-8 within the muscle following intense resistance exercise. Polyphenol supplementation may attenuate the IL-8 response, however, did not affect granulocyte percentage and adhesion molecule expression in peripheral blood following resistance exercise.