A systematic review of the impact of postoperative aerobic exercise training in patients undergoing surgery for intra-abdominal cancers.

INTRODUCTION: Enhanced recovery after surgery (ERAS) programmes which advocate early mobility after surgery have improved immediate clinical outcomes for patients undergoing abdominal cancer resections with curative intent. However, the impact of continued physical activity on patient-related outcomes and functional recovery is not well defined. The aim of this review was to assess the impact of postoperative aerobic exercise training, either alone or in conjunction with another exercise modality, on patients who have had surgery for intra-abdominal cancer. METHODS: A literature search was performed of electronic journal databases. Eligible papers needed to report an outcome of aerobic capacity in patients older than 18 years of age, who underwent cancer surgery with curative intent and participated in an exercise programme (not solely ERAS) that included an aerobic exercise component starting at any point in the postoperative pathway up to 12 weeks. RESULTS: Eleven studies were deemed eligible for inclusion consisting of two inpatient, one mixed inpatient/outpatient and eight outpatient studies. Meta-analysis of four outpatient studies, each reporting change in 6-min walk test (6MWT), showed a significant improvement in 6MWT with exercise (MD 74.92 m, 95% CI 48.52-101.31 m). The impact on health-related quality of life was variable across studies. CONCLUSION: Postoperative exercise confers benefits in improving aerobic function post surgery and can be safely delivered in various formats (home-based or group/supervised).

Impacts of rat hindlimb Fndc5/irisin overexpression on muscle and adipose tissue metabolism.

Myokines, such as irisin, have been purported to exert physiological effects on skeletal muscle in an autocrine/paracrine fashion. In this study, we aimed to investigate the mechanistic role of in vivo fibronectin type III domain-containing 5 (Fndc5)/irisin upregulation in muscle. Overexpression (OE) of Fndc5 in rat hindlimb muscle was achieved by in vivo electrotransfer, i.e., bilateral injections of Fndc5 harboring vectors for OE rats (n = 8) and empty vector for control rats (n = 8). Seven days later, a bolus of D2O (7.2 mL/kg) was administered via oral gavage to quantify muscle protein synthesis. After an overnight fast, on day 9, 2-deoxy-d-glucose-6-phosphate (2-DG6P; 6 mg/kg) was provided during an intraperitoneal glucose tolerance test (2 g/kg) to assess glucose handling. Animals were euthanized, musculus tibialis cranialis muscles and subcutaneous fat (inguinal) were harvested, and metabolic and molecular effects were evaluated. Muscle Fndc5 mRNA increased with OE (~2-fold; P = 0.014), leading to increased circulating irisin (1.5 ± 0.9 to 3.5 ± 1.2 ng/mL; P = 0.049). OE had no effect on protein anabolism or mitochondrial biogenesis; however, muscle glycogen was increased, along with glycogen synthase 1 gene expression (P = 0.04 and 0.02, respectively). In addition to an increase in glycogen synthase activation in OE (P = 0.03), there was a tendency toward increased glucose transporter 4 protein (P = 0.09). However, glucose uptake (accumulation of 2-DG6P) was identical. Irisin elicited no endocrine effect on mitochondrial biogenesis or uncoupling proteins in white adipose tissue. Hindlimb overexpression led to physiological increases in Fndc5/irisin. However, our data indicate limited short-term impacts of irisin in relation to muscle anabolism, mitochondrial biogenesis, glucose uptake, or adipose remodeling.

The efficacy of 'static' training interventions for improving indices of cardiorespiratory fitness in premenopausal females.

PURPOSE: Cardiovascular disease (CVD) is the leading cause of death worldwide. Many risk factors for CVD can be modified pharmacologically; however, uptake of medications is low, especially in asymptomatic people. Exercise is also effective at reducing CVD risk, but adoption is poor with time-commitment and cost cited as key reasons for this. Repeated remote ischaemic preconditioning (RIPC) and isometric handgrip (IHG) training are both inexpensive, time-efficient interventions which have shown some promise in reducing blood pressure (BP) and improving markers of cardiovascular health and fitness. However, few studies have investigated the effectiveness of these interventions in premenopausal women. METHOD: Thirty healthy females were recruited to twelve supervised sessions of either RIPC or IHG over 4 weeks, or acted as non-intervention controls (CON). BP measurements, flow-mediated dilatation (FMD) and cardiopulmonary exercise tests (CPET) were performed at baseline and after the intervention period. RESULTS: IHG and RIPC were both well-tolerated with 100% adherence to all sessions. A statistically significant reduction in both systolic (- 7.2 mmHg) and diastolic (- 6 mmHg) BP was demonstrated following IHG, with no change following RIPC. No statistically significant improvements were observed in FMD or CPET parameters in any group. CONCLUSIONS: IHG is an inexpensive and well-tolerated intervention which may improve BP; a key risk factor for CVD. Conversely, our single arm RIPC protocol, despite being similarly well-tolerated, did not elicit improvements in any cardiorespiratory parameters in our chosen population.

A novel D2O tracer method to quantify RNA turnover as a biomarker of de novo ribosomal biogenesis, in vitro, in animal models, and in human skeletal muscle.

Current methods to quantify in vivo RNA dynamics are limited. Here, we developed a novel stable isotope (D2O) methodology to quantify RNA synthesis (i.e., ribosomal biogenesis) in cells, animal models, and humans. First, proliferating C2C12 cells were incubated in D2O-enriched media and myotubes ±50 ng/ml IGF-I. Second, rat quadriceps (untrained, n = 9; 7-wk interval-"like" training, n = 13) were collected after ~3-wk D2O (70 atom %) administration, with body-water enrichment monitored via blood sampling. Finally, 10 (23 ± 1 yr) men consumed 150-ml D2O followed by 50 ml/wk and undertook 6-wk resistance exercise (6 × 8 repetitions, 75% 1-repetition maximum 3/wk) with body-water enrichment monitored by saliva sampling and muscle biopsies (for determination of RNA synthesis) at 0, 3, and 6 wk. Ribose mole percent excess (r-MPE) from purine nucleotides was analyzed via GC-MS/MS. Proliferating C2C12 cell r-MPE exhibited a rise to plateau, whereas IGF-I increased myotube RNA from 76 ± 3 to 123 ± 3 ng/µl and r-MPE by 0.39 ± 0.1% (both P < 0.01). After 3 wk, rat quadriceps r-MPE had increased to 0.25 ± 0.01% (P < 0.01) and was greater with running exercise (0.36 ± 0.02%; P < 0.01). Human muscle r-MPE increased to 0.06 ± 0.01 and 0.13 ± 0.02% at 3/6 wk, respectively, equating to synthesis rates of ~0.8%/day, increasing with resistance exercise to 1.7 ± 0.3%/day (P < 0.01) and 1.2 ± 0.1%/day (P < 0.05) at 3/6 wk, respectively. Therefore, we have developed and physiologically validated a novel technique to explore ribosomal biogenesis in a multimodal fashion.

An overview of technical considerations for Western blotting applications to physiological research.

The applications of Western/immunoblotting (WB) techniques have reached multiple layers of the scientific community and are now considered routine procedures in the field of physiology. This is none more so than in relation to skeletal muscle physiology (i.e., resolving the mechanisms underpinning adaptations to exercise). Indeed, the inclusion of WB data is now considered an essential aspect of many such physiological publications to provide mechanistic insight into regulatory processes. Despite this popularity, and due to the ubiquitous and relatively inexpensive availability of WB equipment, the quality of WB in publications and subsequent analysis and interpretation of the data can be variable, perhaps resulting in spurious conclusions. This may be due to poor laboratory technique and/or lack of comprehension of the critical steps involved in WB and what quality control procedures should be in place to ensure robust data generation. The present review aims to provide a detailed description and critique of WB procedures and technicalities, from sample collection through preparation, blotting and detection, to analysis of the data collected. We aim to provide the reader with improved expertise to critically conduct, evaluate, and troubleshoot the WB process, to produce reproducible and reliable blots.

A 31-day time to surgery compliant exercise training programme improves aerobic health in the elderly.

BACKGROUND: Over 41,000 people were diagnosed with colorectal cancer (CRC) in the UK in 2011. The incidence of CRC increases with age. Many elderly patients undergo surgery for CRC, the only curative treatment. Such patients are exposed to risks, which increase with age and reduced physical fitness. Endurance-based exercise training programmes can improve physical fitness, but such programmes do not comply with the UK, National Cancer Action Team 31-day time-to-treatment target. High-intensity interval training (HIT) can improve physical performance within 2-4 weeks, but few studies have shown HIT to be effective in elderly individuals, and those who do employ programmes longer than 31 days. Therefore, we investigated whether HIT could improve cardiorespiratory fitness in elderly volunteers, age-matched to a CRC population, within 31 days. METHODS: This observational cohort study recruited 21 healthy elderly participants (8 male and 13 female; age 67 years (range 62-73 years)) who undertook cardiopulmonary exercise testing before and after completing 12 sessions of HIT within a 31-day period. RESULTS: Peak oxygen consumption (VO2 peak) (23.9 ± 4.7 vs. 26.2 ± 5.4 ml/kg/min, p = 0.0014) and oxygen consumption at anaerobic threshold (17.86 ± 4.45 vs. 20.21 ± 4.11 ml/kg/min, p = 0.008) increased after HIT. CONCLUSIONS: It is possible to improve cardiorespiratory fitness in 31 days in individuals of comparable age to those presenting for CRC surgery.

Gefitinib in definitive management of esophageal or gastroesophageal junction cancer: a retrospective analysis of two clinical trials.

The role of epidermal growth factor receptor inhibition in resectable esophageal/gastroesophageal junction (E/GEJ) cancer is uncertain. Results from two Cleveland Clinic trials of concurrent chemoradiotherapy (CCRT) and surgery are updated and retrospectively compared, the second study differing only by the addition of gefitinib (G) to the treatment regimen. Eligibility required a diagnosis of E/GEJ squamous cell or adenocarcinoma, with an endoscopic ultrasound stage of at least T3, N1, or M1a (American Joint Committee on Cancer 6th). Patients in both trials received 5-fluorouracil (1000 mg/m(2) /day) and cisplatin (20 mg/m(2) /day) as continuous infusions over days 1-4 along with 30 Gy radiation at 1.5 Gy bid. Surgery followed in 4-6 weeks; identical CCRT was given 6-10 weeks later. The second trial added G, 250 mg/day, on day 1 for 4 weeks, and again with postoperative CCRT for 2 years. Preliminary results and comparisons have been previously published. Clinical characteristics were similar between the 80 patients on the G trial (2003-2006) and the 93 patients on the no-G trial (1999-2003). Minimum follow-up for all patients was 5 years. Multivariable analyses comparing the G versus no-G patients and adjusting for statistically significant covariates demonstrated improved overall survival (hazard ratio [HR] 0.64, 95% confidence interval [CI] = 0.45-0.91, P = 0.012), recurrence-free survival (HR 0.61, 95% CI = 0.43-0.86, P = 0.006), and distant recurrence (HR 0.68, 95% CI = 0.45-1.00, P = 0.05), but not locoregional recurrence. Although this retrospective comparison can only be considered exploratory, it suggests that G may improve clinical outcomes when combined with CCRT and surgery in the definitive treatment of E/GEJ cancer.

Effects of leucine and its metabolite ß-hydroxy-ß-methylbutyrate on human skeletal muscle protein metabolism.

Maintenance of skeletal muscle mass is contingent upon the dynamic equilibrium (fasted losses-fed gains) in protein turnover. Of all nutrients, the single amino acid leucine (Leu) possesses the most marked anabolic characteristics in acting as a trigger element for the initiation of protein synthesis. While the mechanisms by which Leu is 'sensed' have been the subject of great scrutiny, as a branched-chain amino acid, Leu can be catabolized within muscle, thus posing the possibility that metabolites of Leu could be involved in mediating the anabolic effect(s) of Leu. Our objective was to measure muscle protein anabolism in response to Leu and its metabolite HMB. Using [1,2-(13)C2]Leu and [(2)H5]phenylalanine tracers, and GC-MS/GC-C-IRMS we studied the effect of HMB or Leu alone on MPS (by tracer incorporation into myofibrils), and for HMB we also measured muscle proteolysis (by arteriovenous (A-V) dilution). Orally consumed 3.42 g free-acid (FA-HMB) HMB (providing 2.42 g of pure HMB) exhibited rapid bioavailability in plasma and muscle and, similarly to 3.42 g Leu, stimulated muscle protein synthesis (MPS; HMB +70% vs. Leu +110%). While HMB and Leu both increased anabolic signalling (mechanistic target of rapamycin; mTOR), this was more pronounced with Leu (i.e. p70S6K1 signalling 90 min vs. 30 min for HMB). HMB consumption also attenuated muscle protein breakdown (MPB; -57%) in an insulin-independent manner. We conclude that exogenous HMB induces acute muscle anabolism (increased MPS and reduced MPB) albeit perhaps via distinct, and/or additional mechanism(s) to Leu.

Clinicopathologic features and treatment outcomes of patients with human epidermal growth factor receptor 2-positive adenocarcinoma of the esophagus and gastroesophageal junction.

Human epidermal growth factor receptor 2 (HER2) is overexpressed in 21% of gastric and 33% of gastroesophageal junction (GEJ) adenocarcinomas. Trastuzumab has been approved for metastatic HER2-positive gastric/GEJ cancer in combination with chemotherapy. This retrospective analysis was undertaken to better define the clinicopathologic features, treatment outcomes, and prognosis in patients with HER2-positive adenocarcinoma of the esophagus/GEJ. Pathologic specimens from 156 patients with adenocarcinoma of the esophagus/GEJ treated on clinical trials with chemoradiation and surgery were tested for HER2. Seventy-six patients also received 2 years of gefitinib. Baseline characteristics and treatment outcomes of the HER2-positive and negative patients were compared both in aggregate and separately for each of the two trials. Of 156 patients, 135 had sufficient pathologic material available for HER2 assessment. HER2 positivity was found in 23%; 28% with GEJ primaries and 15% with esophageal primaries (P= 0.10). There was no statistical difference in clinicopathologic features between HER2-positive and negative patients except HER2-negative tumors were more likely to be poorly differentiated (P < 0.001). Locoregional recurrence, distant metastatic recurrence, any recurrence, and overall survival were also statistically similar between the HER2-positive and the HER2-negative groups, in both the entire cohort and in the gefitinib-treated subset. Except for tumor differentiation, HER2-positive and negative patients with adenocarcinoma of the esophagus and GEJ do not differ in clinicopathologic characteristics and treatment outcomes. Given the demonstrated benefit of trastuzumab in HER2-positive gastric cancer and the similar incidence of HER2 overexpression in esophageal/GEJ adenocarcinoma, further evaluation of HER2-directed therapy in this disease seems indicated.

Loss of muscle mass in the immediate post-operative period is associated with inadequate dietary protein and energy intake.

Despite the implementation of 'Enhanced Recovery After Surgery' (ERAS) protocols, major abdominal surgery is still associated with significant and detrimental losses of muscle mass and function in the post-operative period. Although ERAS protocols advocate both early mobility and dietary intake, dietary composition in the immediate post-operative period is poorly characterised, despite muscle losses being greatest in this period. Herein, we show in 15 patients (66 ± 6 y, 12:3 M:F) who lost ~10% m. vastus lateralis muscle mass in the 5 days after open colorectal resective surgery, mean energy intake was only ~25% of the minimum ESPEN recommendation of 25 kcal/kg/d and daily dietary protein intake was only ~12% of the ESPEN recommended guidelines of 1.5 g/kg/d. Given the known importance of nutrition for muscle mass maintenance, innovative dietary interventions are needed in the immediate post-operative period, accounting for specific patient dietary preference to maximise compliance (e.g., soft-textured foods).

Caloric restriction improves glycaemic control without reducing plasma branched-chain amino acids or keto-acids in obese men.

Higher plasma leucine, isoleucine and valine (BCAA) concentrations are associated with diabetes, obesity and insulin resistance (IR). Here, we evaluated the effects of 6-weeks very-low calorie diet (VLCD) upon fasting BCAA in overweight (OW) non-diabetic men, to explore associations between circulating BCAA and IR, before and after a weight loss intervention. Fasting plasma BCAAs were quantified in an OW (n = 26; BMI 32.4 ± 3 kg/m2; mean age 44 ± 9 y) and a normal-weight (NW) group (n = 26; BMI 24 ± 3.1 kg/m2; mean age 32 ± 12.3 y). Ten of the OW group (BMI 32.2 ± 4 kg/m2; 46 ± 8 y) then underwent 6-weeks of VLCD (600-800 kcal/day). Fasting plasma BCAA (gas chromatography-mass spectrometry), insulin sensitivity (HOMA-IR) and body-composition (DXA) were assessed before and after VLCD. Total BCAA were higher in OW individuals (sum leucine/isoleucine/valine: 457 ± 85 µM) compared to NW control individuals (365 ± 78 µM, p < 0.001). Despite significant weight loss (baseline 103.9 ± 12.3 to 93 ± 9.6 kg and BMI 32.2 ± 4 to 28.9 ± 3.6 kg/m2), no changes were observed in BCAAs after 6-weeks of VLCD. Moreover, although VLCD resulted in a significant reduction in HOMA-IR (baseline 1.19 ± 0.62 to 0.51 ± 0.21 post-VLCD; p < 0.001), Pearson's r revealed no relationships between BCAA and HOMA-IR, either before (leucine R2: 2.49e-005, p = 0.98; isoleucine R2: 1.211-e006, p = 0.9; valine R2: 0.004, p = 0.85) or after VLCD (leucine R2: 0.003, p = 0.86; isoleucine R2: 0.006, p = 0.82; valine R2: 0.002, p = 0.65). Plasma BCAA are higher in OW compared to NW individuals. However, while 6-weeks VLCD reduced body weight and IR in OW individuals, this was not associated with reductions in BCAA. This suggests that studies demonstrating links between BCAA and insulin resistance in OW individuals, are complex and are not normalised by simply losing weight.

A collagen hydrolysate/milk protein-blend stimulates muscle anabolism equivalently to an isoenergetic milk protein-blend containing a greater quantity of essential amino acids in older men.

BACKGROUND & AIMS: Nutritional composition is key for skeletal muscle maintenance into older age. Yet the acute effects of collagen protein blended with other protein sources, in relation to skeletal muscle anabolism, are ill-defined. We investigated human muscle protein synthesis (MPS) responses to a 20 g blend of collagen protein hydrolysate + milk protein (CP+MP, 125 ml) oral nutritional supplement (ONS) vs. 20 g non-blended milk protein source (MP, 200 ml) ONS, in older adults. METHODS: Healthy older men (N = 8, 71±1 y, BMI: 27±1 kg·m-2) underwent a randomized trial of 20 g protein, from either a CP+MP blend (Fresubin®3.2 kcal DRINK), or a kcal-matched (higher in essential amino acids (EAA) ONS of MP alone. Vastus lateralis (VL) MPS and plasma AA were determined using stable isotope-tracer mass spectrometry; anabolic signaling was quantified via immuno-blotting in VL biopsies taken at baseline and 2/4 h after ONS feeding. Plasma insulin was measured via enzyme-linked immunosorbent assay (ELISA). Measures were taken at rest, after the feed (FED) and after the feed + exercise (FED-EX) conditions (unilateral leg exercise, 6 × 8, 75% 1-RM). RESULTS: MP resulted in a greater increase in plasma leucine (MP mean: 152 ± 6 µM, CP+MP mean: 113 ± 4 µM (Feed P < 0.001) and EAA (MP mean: 917 ± 25 µM, CP+MP mean: 786 ± 15 µM (Feed P < 0.01) than CP+MP. CP + MP increased plasma glycine (peak 385 ± 57 µM (P < 0.05)), proline (peak 323 ± 29 µM (P < 0.01)) and non-essential amino acids (NEAA) (peak 1621 ± 107 µM (P < 0.01)) with MP showing no increase. Plasma insulin increased in both trials (CP+MP: 58 ± 10 mU/mL (P < 0.01), MP: 42 ± 6 mU/mL (P < 0.01), with peak insulin greater with CP+MP vs. MP (P < 0.01). MPS demonstrated equivalent increases in response to CP+MP and MP under both FED (MP: 0.039 ± 0.005%/h to 0.081 ± 0.014%/h (P < 0.05), CP+MP: 0.042 ± 0.004%/h to 0.085 ± 0.007%/h (P < 0.05)) and FED-EX (MP: 0.039 ± 0.005%/h to 0.093 ± 0.013%/h (P < 0.01), CP+MP: 0.042 ± 0.004%/h to 0.105 ± 0.015%/h, (P < 0.01)) conditions. FED muscle p-mTOR fold-change from baseline increased to a greater extent with CP+MP vs. MP (P < 0.05), whilst FED-EX muscle p-eEF2 fold-change from baseline decreased to a greater extent with CP+MP vs. MP (P < 0.05); otherwise anabolic signaling responses were indistinguishable. CONCLUSION: Fresubin®3.2 kcal DRINK, which contains a 20 g mixed blend of CP+MP, resulted in equivalent MPS responses to MP alone. Fresubin® 3.2 Kcal DRINK may provide a suitable alternative to MP for use in older adults and a convenient way to supplement calories and protein to improve patient adherence and mitigate muscle mass loss.

Current perspectives on defining and mitigating frailty in relation to critical illness.

Up to half of ICU survivors, many of whom were premorbidly well, will have residual functional and/or cognitive impairment and be vulnerable to future health problems. Frailty describes vulnerability to poor resolution of homeostasis after a stressor event but it is not clear whether the vulnerability seen after ICU correlates with clinical measures of frailty. In clinical practice, the scales most commonly used in critically ill patients are based on the assessment of severity and survival. Identification and monitoring of frailty in the ICU may be an alternative or complimentary approach, particularly if it helps explain vulnerability during the recovery and rehabilitation period. The purpose of this review is to discuss the use of tools to assess frailty status in the critically ill, and consider their importance in clinical practice. Amongst these, we consider biomarkers with potential to identify patients at greater or lesser risk of developing post-ICU vulnerability.

Omega-3 supplementation during unilateral resistance exercise training in older women: A within subject and double-blind placebo-controlled trial.

BACKGROUND & AIMS: The skeletal muscle anabolic effects of n-3 polyunsaturated fatty acids (n-3 PUFA) appear favoured towards women; a property that could be exploited in older women who typically exhibit poor muscle growth responses to resistance exercise training (RET). Here we sought to generate novel insights into the efficacy and mechanisms of n-3 PUFA alongside short-term RET in older women. METHODS: We recruited 16 healthy older women (Placebo n = 8 (PLA): 67±1y, n-3 PUFA n = 8: 64±1y) to a randomised double-blind placebo-controlled trial (n-3 PUFA; 3680 mg/day versus PLA) of 6 weeks fully-supervised progressive unilateral RET (i.e. 6 × 8 reps, 75% 1-RM, 3/wk-1). Strength was assessed by knee extensor 1-RM and isokinetic dynamometry âˆ¼ every 10 d. Thigh fat free mass (TFFM) was measured by DXA at 0/3/6 weeks. Bilateral vastus lateralis (VL) biopsies at 0/2/4/6 weeks with deuterium oxide (D2O) dosing were used to determine MPS responses for 0-2 and 4-6 weeks. Further, fibre cross sectional area (CSA), myonuclei number and satellite cell (SC) number were assessed, alongside muscle anabolic/catabolic signalling via immunoblotting. RESULTS: RET increased 1-RM equally in the trained leg of both groups (+23 ± 5% n-3 PUFA vs. +25 ± 5% PLA (both P < 0.01)) with no significant increase in maximum voluntary contraction (MVC) (+10 ± 6% n-3 PUFA vs. +13 ± 5% PLA). Only the n-3 PUFA group increased TFFM (3774 ± 158 g to 3961 ± 151 g n-3 PUFA (P < 0.05) vs. 3406 ± 201 g to 3561 ± 170 PLA) and type II fibre CSA (3097 ± 339 µm2 to 4329 ± 264 µm2 n-3 PUFA (P < 0.05) vs. 2520 ± 316 µm2 to 3467 ± 303 µm2 in PL) with RET. Myonuclei number increased equally in n-3 PUFA and PLA in both type I and type II fibres, with no change in SC number. N-3 PUFA had no added benefit on muscle protein synthesis (MPS), however, during weeks 4-6 of RET, absolute synthesis rates (ASR) displayed a trend to increase with n-3 PUFA only (5.6 ± 0.3 g d-1 to 7.1 ± 0.5 g d-1 n-3 PUFA (P = 0.09) vs. 5.5 ± 0.5 g d-1 to 6.5 ± 0.5 g d-1 PLA). Further, the n-3 PUFA group displayed greater 4EBP1 activation after acute RE at 6 weeks. CONCLUSION: n3-PUFA enhanced RET gains in muscle mass through type II fibre hypertrophy, with data suggesting a role for MPS rather than via SC recruitment. As such, the present study adds to a literature base illustrating the apparent enhancement of muscle hypertrophy with RET in older women fed adjuvant n3-PUFA.

High-intensity interval training produces a significant improvement in fitness in less than 31 days before surgery for urological cancer: a randomised control trial.

OBJECTIVES: To assess the efficacy of high-intensity interval training (HIIT) for improving cardiorespiratory fitness (CRF) in patients awaiting resection for urological malignancy within four weeks. SUBJECTS/PATIENTS AND METHODS: A randomised control trial of consecutive patients aged (>65 years) scheduled for major urological surgery in a large secondary referral centre in a UK hospital. The primary outcome is change in anaerobic threshold (VO2AT) following HIIT vs. standard care. RESULTS: Forty patients were recruited (mean age 72 years, male (39): female (1)) with 34 completing the protocol. Intention to treat analysis showed significant improvements in anaerobic threshold (VO2AT; mean difference (MD) 2.26 ml/kg/min (95% CI 1.25-3.26)) following HIIT. Blood pressure (BP) also significantly reduced in following: HIIT (SBP: -8.2 mmHg (95% CI -16.09 to -0.29) and DBP: -6.47 mmHg (95% CI -12.56 to -0.38)). No reportable adverse safety events occurred during HIIT and all participants achieved >85% predicted maximum heart rate during sessions, with protocol adherence of 84%. CONCLUSIONS: HIIT can improve CRF and cardiovascular health, representing clinically meaningful and achievable pre-operative improvements. Larger randomised trials are required to investigate the efficacy of prehabilitation HIIT upon different cancer types, post-operative complications, socio-economic impact and long-term survival.

A double-blind placebo controlled trial into the impacts of HMB supplementation and exercise on free-living muscle protein synthesis, muscle mass and function, in older adults.

Age-related sarcopenia and dynapenia are associated with frailty and metabolic diseases. Resistance exercise training (RET) adjuvant to evidence-based nutritional intervention(s) have been shown as mitigating strategies. Given that ß-hydroxy-ß-methyl-butyrate (HMB) supplementation during RET improves lean body mass in younger humans, and that we have shown that HMB acutely stimulates muscle protein synthesis (MPS) and inhibits breakdown; we hypothesized that chronic supplementation of HMB free acid (HMB-FA) would enhance MPS and muscle mass/function in response to RET in older people. We recruited 16 healthy older men (Placebo (PLA): 68.5 ± 1.0 y, HMB-FA: 67.8 ± 1.15 y) for a randomised double-blind-placebo controlled trial (HMB-FA 3 × 1 g/day vs. PLA) involving a 6-week unilateral progressive RET regime (6 × 8 repetitions, 75% 1-RM, 3 · wk-1). Deuterium oxide (D2O) dosing was performed over the first two weeks (0-2 wk) and last two weeks (4-6 wk) with bilateral vastus lateralis (VL) biopsies at 0-2 and 4-6 wk (each time 75 ± 2 min after a single bout of resistance exercise (RE)) for quantification of early and later MPS responses and post-RE myogenic gene expression. Thigh lean mass (TLM) was measured by DXA, VL thickness and architecture (fibre length and pennation angle) by ultrasound at 0/3/6 wk, and strength by knee extensor 1-RM testing and MVC by isokinetic dynamometry (approx. every 10 days). RET induced strength increases (1-RM) in the exercised leg of both groups (398 ± 22N to 499 ± 30N HMB-FA vs. 396 ± 29N to 510 ± 43N PLA (both P < 0.05)). In addition, maximal voluntary contraction (MVC) also increased (179 ± 12 Nm to 203 ± 12 Nm HMB-FA vs. 185 ± 10 Nm to 217 ± 11 Nm PLA (both P < 0.05); with no group differences. VL muscle thickness increased significantly in the exercised leg in both groups, with no group differences. TLM (by DXA) rose to significance only in the HMB-FA group (by 5.8%-5734 ± 245 g p = 0.015 vs. 3.0% to 5644 ± 323 g P = 0.06 in PLA). MPS remained unchanged in the untrained legs (UT) 0-2 weeks being 1.06 ± 0.08%.d-1 (HMB-FA) and 1.14 ± 0.09%.d-1 (PLA), the trained legs (T) exhibited increased MPS in the HMB-FA group only at 0-2-weeks (1.39 ± 0.10%.d-1, P < 0.05) compared with UT: but was not different at 4-6-weeks: 1.26 ± 0.05%.d-1. However, there were no significant differences in MPS between the HMB-FA and PLA groups at any given time point and no significant treatment interaction observed. We also observed significant inductions of c-Myc gene expression following each acute RE bout, with no group differences. Further, there were no changes in any other muscle atrophy/hypertrophy or myogenic transcription factor genes we measured. RET with adjuvant HMB-FA supplements in free-living healthy older men did not enhance muscle strength or mass greater than that of RET alone (PLA). That said, only HMB-FA increased TLM, supported by early increases in chronic MPS. As such, chronic HMB-FA supplementation may result in long term benefits in older males, however longer and larger studies may be needed to fully determine the potential effects of HMB-FA supplementation; translating to any functional benefit.

Impact of the calcium form of ß-hydroxy-ß-methylbutyrate upon human skeletal muscle protein metabolism.

BACKGROUND & AIMS: ß-hydroxy-ß-methylbutyrate (HMB) is purported as a key nutritional supplement for the preservation of muscle mass in health, disease and as an ergogenic aid in exercise. Of the two available forms of HMB (calcium (Ca-HMB) salt or free acid (FA-HMB)) - differences in plasma bioavailability have been reported. We previously reported that ∼3 g oral FA-HMB increased muscle protein synthesis (MPS) and reduced muscle protein breakdown (MPB). The objective of the present study was to quantify muscle protein metabolism responses to oral Ca-HMB. METHODS: Eight healthy young males received a primed constant infusion of 1,2 13C2 leucine and 2H5 phenylalanine to assess MPS (by tracer incorporation in myofibrils) and MPB (via arterio-venous (A-V) dilution) at baseline and following provision of ∼3 g of Ca-HMB; muscle anabolic (MPS) and catabolic (MPB) signalling was assessed via immunoblotting. RESULTS: Ca-HMB led a significant and rapid (<60 min) peak in plasma HMB concentrations (483.6 ± 14.2 µM, p < 0.0001). This rise in plasma HMB was accompanied by increases in MPS (PA: 0.046 ± 0.004%/h, CaHMB: 0.072 ± 0.004%/h, p < 0001) and suppressions in MPB (PA: 7.6 ± 1.2 µmol Phe per leg min-1, Ca-HMB: 5.2 ± 0.8 µmol Phe per leg min-1, p < 0.01). Increases in the phosphorylation of mTORc1 substrates i.e. p70S6K1 and RPS6 were also observed, with no changes detected in the MPB targets measured. CONCLUSIONS: These findings support the pro-anabolic properties of HMB via mTORc1, and show that despite proposed differences in bioavailability, Ca-HMB provides a comparable stimulation to MPS and suppression of MPB, to FA-HMB, further supporting its use as a pharmaconutrient in the modulation of muscle mass.

Skeletal muscle homeostasis and plasticity in youth and ageing: impact of nutrition and exercise.

Skeletal muscles comprise a substantial portion of whole body mass and are integral for locomotion and metabolic health. Increasing age is associated with declines in both muscle mass and function (e.g. strength-related performance, power) with declines in muscle function quantitatively outweighing those in muscle volume. The mechanisms behind these declines are multi-faceted involving both intrinsic age-related metabolic dysregulation and environmental influences such as nutritional and physical activity. Ageing is associated with a degree of 'anabolic resistance' to these key environmental inputs, which likely accelerates the intrinsic processes driving ageing. On this basis, strategies to sensitize and/or promote anabolic responses to nutrition and physical activity are likely to be imperative in alleviating the progression and trajectory of sarcopenia. Both resistance- and aerobic-type exercises are likely to confer functional and health benefits in older age, and a clutch of research suggests that enhancement of anabolic responsiveness to exercise and/or nutrition may be achieved by optimizing modifications of muscle-loading paradigms (workload, volume, blood flow restriction) or nutritional support (e.g. essential amino acid/leucine) patterns. Nonetheless, more work is needed in which a more holistic view in ageing studies is taken into account. This should include improved characterization of older study recruits, that is physical activity/nutritional behaviours, to limit confounding variables influencing whether findings are attributable to age, or other environmental influences. Nonetheless, on balance, ageing is associated with declines in muscle mass and function and a partially related decline in aerobic capacity. There is also good evidence that metabolic flexibility is impaired in older age.

Suppressor cells and their role in the survival of immunologically enhanced rat kidney allografts.

A search has been made for suppressor cells in the spleens of AS rats bearing long-surviving, enhanced AUG strain kidney allografts. The assay consisted of an adoptive transfer of splenocytes from AS rats with enhanced AUG kidneys to normal AS rats that also received test grafts of AUG kidneys. The critical feature of the AUG kidney test grafts was that the native population of passenger cells had been replaced by AS passenger cells--thus reducing, but not eliminating, immunogenicity of the graft. With this assay, it was shown that 2.7-3.5 X 10(8) spleen cells transferred substantial and statistically significant suppression of graft rejection. Suppression was also transferred by spleen cells that did not adhere to nylon wool. It is concluded that suppressor cells are one of the mechanisms ensuring continued survival of enhanced kidney allografts.