Quantifying the relationship and contribution of mitochondrial respiration to systemic exercise limitation in heart failure.

AIMS: Heart failure with reduced ejection fraction (HFrEF) induces skeletal muscle mitochondrial abnormalities that contribute to exercise limitation; however, specific mitochondrial therapeutic targets remain poorly established. This study quantified the relationship and contribution of distinct mitochondrial respiratory states to prognostic whole-body measures of exercise limitation in HFrEF. METHODS AND RESULTS: Male patients with HFrEF (n = 22) were prospectively enrolled and underwent ramp-incremental cycle ergometry cardiopulmonary exercise testing to determine exercise variables including peak pulmonary oxygen uptake (V̇O2peak ), lactate threshold (V̇O2LT ), the ventilatory equivalent for carbon dioxide (V̇E /V̇CO2LT ), peak circulatory power (CircPpeak ), and peak oxygen pulse. Pectoralis major was biopsied for assessment of in situ mitochondrial respiration. All mitochondrial states including complexes I, II, and IV and electron transport system (ETS) capacity correlated with V̇O2peak (r = 0.40-0.64; P < 0.05), V̇O2LT (r = 0.52-0.72; P < 0.05), and CircPpeak (r = 0.42-0.60; P < 0.05). Multiple regression analysis revealed that combining age, haemoglobin, and left ventricular ejection fraction with ETS capacity could explain 52% of the variability in V̇O2peak and 80% of the variability in V̇O2LT , respectively, with ETS capacity (P = 0.04) and complex I (P = 0.01) the only significant contributors in the model. CONCLUSIONS: Mitochondrial respiratory states from skeletal muscle biopsies of patients with HFrEF were independently correlated to established non-invasive prognostic cycle ergometry cardiopulmonary exercise testing indices including V̇O2peak , V̇O2LT , and CircPpeak . When combined with baseline patient characteristics, over 50% of the variability in V̇O2peak could be explained by the mitochondrial ETS capacity. These data provide optimized mitochondrial targets that may attenuate exercise limitations in HFrEF.

Protein supplementation increases adaptations to endurance training: A systematic review and meta-analysis.

BACKGROUND: Trials that assessed the impact of protein supplementation on endurance training adaptations have reported conflicting findings. OBJECTIVE: To determine the impact of protein supplementation during chronic endurance training on aerobic capacity, body composition and exercise performance in healthy and clinical populations. DESIGN: A systematic database search was conducted for randomised controlled trials addressing the effects of protein supplementation during endurance training on aerobic capacity, body composition and exercise performance in PubMed, Embase, Web of Science, and CINAHL. Meta-analyses were performed to outline the overall effects of protein supplementation with all studies containing endurance training components. The effects of endurance training and add-on effects of protein supplementation were evaluated by the meta-analyses with endurance training-focused studies. RESULTS: Nineteen studies and 1162 participants contributed to the analyses. Compared with the control group, the protein supplementation group demonstrated greater improvements in aerobic capacity measured by mixed peak oxygen uptake (V̇O2peak) and peak workload power (Wpeak) (standardised mean difference [SMD] = 0.36, 95% confidence interval [CI]: 0.05 to 0.67), and V̇O2peak (mean difference [MD] = 0.89 mL‧kg-1‧min-1, 95% CI: 0.07 to 1.70); had a greater lean mass gain (MD = 0.32 kg, 95% CI: 0.07 to 0.58); and had a greater improvement in time trial performance (MD = -29.1s, 95% CI:-55.3 to -3.0). Secondary analyses showed that, in addition to the substantial improvement in V̇O2peak (MD = 3.67 mL‧kg-1‧min-1, 95% CI: 2.32 to 5.03) attributed to endurance training, protein supplementation provided an additional 26.4% gain in V̇O2peak (MD = 0.97 mL‧kg-1‧min-1, 95% CI: -0.03 to 1.97). CONCLUSION: Protein supplementation further increased aerobic capacity, stimulated lean mass gain, and improved time trial performance during chronic endurance training in healthy and clinical populations. PROSPERO REGISTRATION NUMBER: (CRD42020155239).

Impact of protein supplementation during endurance training on changes in skeletal muscle transcriptome.

BACKGROUND: Protein supplementation improves physiological adaptations to endurance training, but the impact on adaptive changes in the skeletal muscle transcriptome remains elusive. The present analysis was executed to determine the impact of protein supplementation on changes in the skeletal muscle transcriptome following 5-weeks of endurance training. RESULTS: Skeletal muscle tissue samples from the vastus lateralis were taken before and after 5-weeks of endurance training to assess changes in the skeletal muscle transcriptome. One hundred and 63 genes were differentially expressed after 5-weeks of endurance training in both groups (q-value< 0.05). In addition, the number of genes differentially expressed was higher in the protein group (PRO) (892, q-value< 0.05) when compared with the control group (CON) (440, q-value< 0.05), with no time-by-treatment interaction effect (q-value> 0.05). Endurance training primarily affected expression levels of genes related to extracellular matrix and these changes tended to be greater in PRO than in CON. CONCLUSIONS: Protein supplementation subtly impacts endurance training-induced changes in the skeletal muscle transcriptome. In addition, our transcriptomic analysis revealed that the extracellular matrix may be an important factor for skeletal muscle adaptation in response to endurance training. This trial was registered at clinicaltrials.gov as NCT03462381, March 12, 2018. TRIAL REGISTRATION: This trial was registered at clinicaltrials.gov as NCT03462381.

Protein supplementation elicits greater gains in maximal oxygen uptake capacity and stimulates lean mass accretion during prolonged endurance training: a double-blind randomized controlled trial.

BACKGROUND: Endurance training induces numerous cardiovascular and skeletal muscle adaptations, thereby increasing maximal oxygen uptake capacity (VO2max). Whether protein supplementation enhances these adaptations remains unclear. OBJECTIVE: The present study was designed to determine the impact of protein supplementation on changes in VO2max during prolonged endurance training. METHODS: We used a double-blind randomized controlled trial with repeated measures among 44 recreationally active, young males. Subjects performed 3 endurance training sessions per week for 10 wk. Supplements were provided immediately after each exercise session and daily before sleep, providing either protein (PRO group; n = 19; 21.5 ± 0.4 y) or an isocaloric amount of carbohydrate as control (CON group; n = 21; 22.5 ± 0.5 y). The VO2max, simulated 10-km time trial performance, and body composition (dual-energy X-ray absorptiometry) were measured before and after 5 and 10 wk of endurance training. Fasting skeletal muscle tissue samples were taken before and after 5 and 10 wk to measure skeletal muscle oxidative capacity, and fasting blood samples were taken every 2 wk to measure hematological factors. RESULTS: VO2max increased to a greater extent in the PRO group than in the CON group after 5 wk (from 49.9 ± 0.8 to 54.9 ± 1.1 vs 50.8 ± 0.9 to 53.0 ± 1.1 mL · kg-1 · min-1; P < 0.05) and 10 wk (from 49.9 ± 0.8 to 55.4 ± 0.9 vs 50.8 ± 0.9 to 53.9 ± 1.2 mL · kg-1 · min-1; P < 0.05). Lean body mass increased in the PRO group whereas lean body mass in the CON group remained stable during the first 5 wk (1.5 ± 0.2 vs 0.1 ± 0.3 kg; P < 0.05) and after 10 wk (1.5 ± 0.3 vs 0.4 ± 0.3 kg; P < 0.05). Throughout the intervention, fat mass reduced significantly in the PRO group and there were no changes in the CON group after 5 wk (-0.6 ± 0.2 vs -0.1 ± 0.2 kg; P > 0.05) and 10 wk (-1.2 ± 0.4 vs -0.2 ± 0.2 kg; P < 0.05). CONCLUSIONS: Protein supplementation elicited greater gains in VO2max and stimulated lean mass accretion but did not improve skeletal muscle oxidative capacity and endurance performance during 10 wk of endurance training in healthy, young males. This trial was registered at clinicaltrials.gov as NCT03462381.

Protein and the Adaptive Response With Endurance Training: Wishful Thinking or a Competitive Edge?

The significance of carbohydrates for endurance training has been well established, whereas the role of protein and the adaptive response with endurance training is unclear. Therefore, the aim of this perspective is to discuss the current evidence on the role of dietary protein and the adaptive response with endurance training. On a metabolic level, a single bout of endurance training stimulates the oxidation of several amino acids. Although the amount of amino acids as part of total energy expenditure during exercise is relatively low compared to other substrates (e.g., carbohydrates and fat), it may depress the rates of skeletal muscle protein synthesis, and thereby have a negative effect on training adaptation. A low supply of amino acids relative to that of carbohydrates may also have negative effects on the synthesis of capillaries, synthesis and turn-over of mitochondrial proteins and proteins involved in oxygen transport including hamoglobin and myoglobin. Thus far, the scientific evidence demonstrating the significance of dietary protein is mainly derived from research with resistance exercise training regimes. This is not surprising since the general paradigm states that endurance training has insignificant effects on skeletal muscle growth. This could have resulted in an underappreciation of the role of dietary protein for the endurance athlete. To conclude, evidence of the role of protein on endurance training adaptations and performance remains scarce and is mainly derived from acute exercise studies. Therefore, future human intervention studies must unravel whether dietary protein is truly capable of augmenting endurance training adaptations and ultimately performance.

Plasma cytokine responses to resistance exercise with different nutrient availability on a concurrent exercise day in trained healthy males.

Carbohydrate availability is proposed as a potential regulator of cytokine responses. We aimed to evaluate the effect of a preresistance exercise carbohydrate meal versus fat meal on plasma cytokine responses to resistance exercise after an endurance exercise earlier that day. Thirteen young, healthy, recreationally active males performed two experimental days with endurance exercise in the morning and resistance exercise in the afternoon. Either a carbohydrate (110 g carbohydrate, 52 g protein, 9 g fat; ~750 kcal) or an isocaloric fat meal (20 gr carbohydrate, 52 g protein, 51 g fat) was provided 2 h before resistance exercise. Blood was taken at baseline and at regular time intervals to measure circulating plasma cytokine levels (e.g. IL-6, IL-8, IL-10, IL-15, TNFα, ANGPTL4, decorin and MCP-1). Plasma glucose and insulin were higher in the postprandial period before the start of the resistance exercise on the carbohydrate condition, while free fatty acids were reduced. At 2 h postresistance exercise, IL-6 concentrations were higher in the fat condition compared to the carbohydrate condition (P < 0.05). In addition, in both conditions IL-6 levels were higher at all time points compared with baseline (P < 0.05). The pattern of increase in plasma IL-8 and IL-10 did not differ significantly between conditions (P > 0.05). There were no differences between conditions on TNFα levels and levels remain constant when compared with baseline (P > 0.05). ANGPTL4, IL-15, Decorin and MCP-1 showed no differences between the fat and carbohydrate condition (P > 0.05). The composition of the pre-exercise meal did in general not influence cytokine responses in the postresistance exercise period, except postresistance exercise circulating plasma IL-6 levels being higher in the fat condition compared with carbohydrate. Our findings support the view that pre-exercise carbohydrate availability does not have a major impact on acute responses of circulating plasma cytokines in humans.

Select Skeletal Muscle mRNAs Related to Exercise Adaptation Are Minimally Affected by Different Pre-exercise Meals that Differ in Macronutrient Profile.

Background: Substantial research has been done on the impact of carbohydrate and fat availability on endurance exercise adaptation, though its role in the acute adaptive response to resistance exercise has yet to be fully characterized. Purpose: We aimed to assess the effects of a pre-resistance exercise isocaloric mixed meal containing different amounts of carbohydrates and fat, on post-resistance exercise gene expression associated with muscle adaptation. Methods: Thirteen young (age 21.2 ± 1.6 year), recreationally trained (VO2max 51.3 ± 4.8 ml/kg/min) men undertook an aerobic exercise session of 90-min continuous cycling (70% VO2max) in the morning with pre- and post-exercise protein ingestion (10 and 15 g casein in a 500 ml beverage pre- and post-exercise, respectively). Subjects then rested for 2 h and were provided with a meal consisting of either 3207 kJ; 52 g protein; 51 g fat; and 23 g carbohydrate (FAT) or 3124 kJ; 53 g protein; 9 g fat; and 109 g carbohydrate (CHO). Two hours after the meal, subjects completed 5 × 8 repetitions (80% 1-RM) for both bilateral leg press and leg extension directly followed by 25 g of whey protein (500 ml beverage). Muscle biopsies were obtained from the vastus lateralis at baseline (morning) and 1 and 3 h post-resistance exercise (afternoon) to determine intramuscular mRNA response. Results: Muscle glycogen levels were significantly decreased post-resistance exercise, without any differences between conditions. Plasma free fatty acids increased significantly after the mixed meal in the FAT condition, while glucose and insulin were higher in the CHO condition. However, PDK4 mRNA quantity was significantly higher in the FAT condition at 3 h post-resistance exercise compared to CHO. HBEGF, INSIG1, MAFbx, MURF1, SIRT1, and myostatin responded solely as a result of exercise without any differences between the CHO and FAT group. FOXO3A, IGF-1, PGC-1α, and VCP expression levels remained unchanged over the course of the day. Conclusion: We conclude that mRNA quantity associated with muscle adaptation after resistance exercise is not affected by a difference in pre-exercise nutrient availability. PDK4 was differentially expressed between CHO and FAT groups, suggesting a potential shift toward fat oxidation and reduced glucose oxidation in the FAT group.

Attenuated strength gains during prolonged resistance exercise training in older adults with high inflammatory status.

OBJECTIVES: Chronic systemic low grade inflammation is associated with the age-related loss of muscle mass. Resistance exercise has been suggested to reduce or lower chronic systemic low grade inflammation. However, systemic chronic low-grade inflammation may adversely affect the adaptive response to exercise training. We investigated the effect of resistance exercise training on systemic chronic low-grade inflammation in older adults. In addition, we studied the association between systemic chronic low-grade inflammation and the adaptive response to exercise training. DESIGN/SETTING/PARTICIPANTS: Frail and pre-frail older adults (61 subjects) performed 24 weeks of progressive resistance exercise training. Frailty was assessed using the Fried frailty criteria. MEASUREMENTS: Lean body mass (DXA), strength (1RM), circulating levels of IL-1ß, IL-6, IL-8 and TNF-α were measured prior to exercise training, after 12 weeks of training, and after 24 weeks of training. RESULTS: Prolonged progressive resistance exercise training did not affect circulating levels of IL-6, IL-8 and TNF-α. However, exercise training led to a small but significant increase of 0.052 pg/mL in IL-1ß. Higher circulating levels of TNF-α, IL-8 and IL-6 during the training period were negatively associated with strength gains for the leg press. A doubling of plasma TNF-α, IL-8 or IL-6 resulted in reduced strength gains for leg press with coefficients of -3.52, -3.42 and -1.54 respectively. High levels of circulating TNF-α were also associated with decreased strength gains for the leg extension (coefficient -1.50). Inflammatory cytokines did not appear to have an effect on gains in lean mass. CONCLUSION: Our findings suggest that increased levels of plasma cytokines (TNF-α, IL-6 and IL-8) are associated with lower strength gains during resistance exercise training.

Glycogen availability and skeletal muscle adaptations with endurance and resistance exercise.

It is well established that glycogen depletion affects endurance exercise performance negatively. Moreover, numerous studies have demonstrated that post-exercise carbohydrate ingestion improves exercise recovery by increasing glycogen resynthesis. However, recent research into the effects of glycogen availability sheds new light on the role of the widely accepted energy source for adenosine triphosphate (ATP) resynthesis during endurance exercise. Indeed, several studies showed that endurance training with low glycogen availability leads to similar and sometimes even better adaptations and performance compared to performing endurance training sessions with replenished glycogen stores. In the case of resistance exercise, a few studies have been performed on the role of glycogen availability on the early post-exercise anabolic response. However, the effects of low glycogen availability on phenotypic adaptations and performance following prolonged resistance exercise remains unclear to date. This review summarizes the current knowledge about the effects of glycogen availability on skeletal muscle adaptations for both endurance and resistance exercise. Furthermore, it describes the role of glycogen availability when both exercise modes are performed concurrently.