-
1.
Pre-sleep Protein Ingestion Increases Mitochondrial Protein Synthesis Rates During Overnight Recovery from Endurance Exercise: A Randomized Controlled Trial.
Trommelen, J, van Lieshout, GAA, Pabla, P, Nyakayiru, J, Hendriks, FK, Senden, JM, Goessens, JPB, van Kranenburg, JMX, Gijsen, AP, Verdijk, LB, et al
Sports medicine (Auckland, N.Z.). 2023;53(7):1445-1455
-
-
-
Free full text
-
Plain language summary
Protein intake prior to overnight sleep has been shown to stimulate muscle protein synthesis overnight and increase muscle mass. This randomised, placebo-controlled, double-blind study of 36 healthy young men compared the effects of pre-sleep casein and whey protein, following a bout of endurance training in the evening. Outcome measures were overnight protein synthesis rates in microfibrils (the contractile organelle of muscle cells) and mitochondria (the energy producing organelle). Ingestion of whey protein resulted in a statistically significantly higher rates of both microfibrillar and mitochondrial protein synthesis compared to placebo. Results for casein were intermediate and not significantly different from either placebo or whey. Both casein and whey protein intake led to a significant increase in circulating total and essential amino acids overnight, compared to placebo, with the whey protein leading to a quicker and casein to a slower but more sustained increase, although the overall increase (area under the curve) did not differ between the two protein groups. There were no differences in sleep, hunger or energy intake at breakfast between groups. The authors conclude that pre-sleep protein intake following endurance exercise increases both microfibrillar and mitochondrial protein synthesis overnight, with casein not being superior to whey.
Abstract
BACKGROUND Casein protein ingestion prior to sleep has been shown to increase myofibrillar protein synthesis rates during overnight sleep. It remains to be assessed whether pre-sleep protein ingestion can also increase mitochondrial protein synthesis rates. Though it has been suggested that casein protein may be preferred as a pre-sleep protein source, no study has compared the impact of pre-sleep whey versus casein ingestion on overnight muscle protein synthesis rates. OBJECTIVE We aimed to assess the impact of casein and whey protein ingestion prior to sleep on mitochondrial and myofibrillar protein synthesis rates during overnight recovery from a bout of endurance-type exercise. METHODS Thirty-six healthy young men performed a single bout of endurance-type exercise in the evening (19:45 h). Thirty minutes prior to sleep (23:30 h), participants ingested 45 g of casein protein, 45 g of whey protein, or a non-caloric placebo. Continuous intravenous L-[ring-13C6]-phenylalanine infusions were applied, with blood and muscle tissue samples being collected to assess overnight mitochondrial and myofibrillar protein synthesis rates. RESULTS Pooled protein ingestion resulted in greater mitochondrial (0.087 ± 0.020 vs 0.067 ± 0.016%·h-1, p = 0.005) and myofibrillar (0.060 ± 0.014 vs 0.047 ± 0.011%·h-1, p = 0.012) protein synthesis rates when compared with placebo. Casein and whey protein ingestion did not differ in their capacity to stimulate mitochondrial (0.082 ± 0.019 vs 0.092 ± 0.020%·h-1, p = 0.690) and myofibrillar (0.056 ± 0.009 vs 0.064 ± 0.018%·h-1, p = 0.440) protein synthesis rates. CONCLUSIONS Protein ingestion prior to sleep increases both mitochondrial and myofibrillar protein synthesis rates during overnight recovery from exercise. The overnight muscle protein synthetic response to whey and casein protein does not differ. CLINICAL TRIAL REGISTRATION NTR7251 .
-
2.
Molecular Regulators of Muscle Mass and Mitochondrial Remodeling Are Not Influenced by Testosterone Administration in Young Women.
Horwath, O, Moberg, M, Hirschberg, AL, Ekblom, B, Apró, W
Frontiers in endocrinology. 2022;13:874748
-
-
-
Free full text
Plain language summary
Testosterone is a sex hormone normally found in higher amounts in adult males than females. Testosterone plays a number of important roles, including influencing muscle size and strength. Treatment with testosterone has been shown to increase lean mass and muscle strength in women as well as men. However, female-only studies are limited, and the precise mechanisms underlying these changes are not well understood. This randomised control trial examined the effect of testosterone administration on regulators of muscle protein turnover and mitochondrial function in muscle samples collected from young women. 48 healthy, pre-menopausal women were assigned to receive either 10mg of transdermal testosterone gel per day, or a placebo, for 10 weeks. Muscle samples were collected via biopsy before and after the intervention. Testosterone administration did not appear to have a significant effect on androgen receptors, 5-alpha reductase, anabolic signalling, or mitochondrial remodelling in muscle tissue. The researchers concluded that improvements in muscle size and oxidative capacity following testosterone administration cannot be explained by changes in protein expression related to muscle protein turnover or mitochondrial remodelling. The authors went on to suggest that the small sample size in this study may have reduced the ability to detect small but biologically relevant changes in protein levels. Within the research, there is large variability among studies in terms of sex, age, route of administration and length of treatment, which makes putting these findings into context of the wider literature difficult.
Abstract
Testosterone (T) administration has previously been shown to improve muscle size and oxidative capacity. However, the molecular mechanisms underlying these adaptations in human skeletal muscle remain to be determined. Here, we examined the effect of moderate-dose T administration on molecular regulators of muscle protein turnover and mitochondrial remodeling in muscle samples collected from young women. Forty-eight healthy, physically active, young women (28 ± 4 years) were assigned in a random double-blind fashion to receive either T (10 mg/day) or placebo for 10-weeks. Muscle biopsies collected before and after the intervention period were divided into sub-cellular fractions and total protein levels of molecular regulators of muscle protein turnover and mitochondrial remodeling were analyzed using Western blotting. T administration had no effect on androgen receptor or 5α-reductase levels, nor on proteins involved in the mTORC1-signaling pathway (mTOR, S6K1, eEF2 and RPS6). Neither did it affect the abundance of proteins associated with proteasomal protein degradation (MAFbx, MuRF-1 and UBR5) and autophagy-lysosomal degradation (AMPK, ULK1 and p62). T administration also had no effect on proteins in the mitochondria enriched fraction regulating mitophagy (Beclin, BNIP3, LC3B-I, LC3B-II and LC3B-II/I ratio) and morphology (Mitofilin), and it did not alter the expression of mitochondrial fission- (FIS1 and DRP1) or fusion factors (OPA1 and MFN2). In summary, these data indicate that improvements in muscle size and oxidative capacity in young women in response to moderate-dose T administration cannot be explained by alterations in total expression of molecular factors known to regulate muscle protein turnover or mitochondrial remodeling.
-
3.
Urolithin A improves muscle strength, exercise performance, and biomarkers of mitochondrial health in a randomized trial in middle-aged adults.
Singh, A, D'Amico, D, Andreux, PA, Fouassier, AM, Blanco-Bose, W, Evans, M, Aebischer, P, Auwerx, J, Rinsch, C
Cell reports. Medicine. 2022;3(5):100633
-
-
-
-
Free full text
Plain language summary
A gradual decline in muscle mass and strength with aging is natural, however, environmental factors such as diet and exercise dictate the trajectory of the decline. Exercise and healthy nutrition are the primary interventions to prevent and manage age-associated decline in muscle health and metabolic diseases. This study was designed as a proof-of-concept investigation of the efficacy of long-term oral supplementation with urolithin A (UA) on physiological endpoints in middle-aged adults. This study is a randomised, double-blind, placebo-controlled study. An overweight middle-aged population with a high body mass index and average physical endurance was selected for the study. Results showed improved lower-body muscle strength in the hamstring skeletal muscle at both doses of UA. Furthermore, it positively impacted aerobic endurance and physical-performance measures such as walking distance. Authors conclude that supplementation with UA is safe and increases circulating levels of UA.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Mitochondrial dysfunction is associated with ageing and linked to deterioration of skeletal muscle and sarcopenia. Improving mitochondrial health may therefore help to improve muscle health as we age.
- Previous studies have demonstrated improvements in muscle endurance with long term UA intake in older adults (1) and the study by Singh et al. supports these findings in middle-aged adults.
- For middle-aged clients who are noticing a decline in muscle strength, exercise performance, or a general increase in fatigue, taking 500-1,000 mg UA daily for two to four months could lead to noticeable improvements in symptoms.
- The compounds from which UA is derived are also found in polyphenol-rich plant foods including pomegranates, berries and walnuts, therefore consuming these foods may be useful dietary additions for the same purpose.
- These findings are likely to be relevant for younger populations too, as mitophagy, which is part of the action of UA, contributes to the removal and recycling of dysfunctional mitochondria, allowing healthier intact mitochondria to take their place.
Evidence Category:
-
X
A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
-
B: Systematic reviews including RCTs of limited number
-
C: Non-randomized trials, observational studies, narrative reviews
-
D: Case-reports, evidence-based clinical findings
-
E: Opinion piece, other
Summary Review:
- Urolithin A (UA) is a microbiome metabolite – known as a postbiotic - of elligitannins and polyphenolic compounds found in some plant foods including pomegratate, berries and walnuts.
- In animal models, UA has previously been shown to have a range of potential health benefits involving induction of mitophagy and on mitochondrial function, as well as on disease states including osteoarthritis, inflammatory bowel disease, cardiovascular disease, and neurodegenerative disorders.
- The current study sought to establish proof-of-concept of the efficacy and safety of long-term UA supplementation on physiological endpoints in middle-aged adults.
- The primary outcome was peak power output and secondary outcomes included a range of clinical and physiological parameters linked to muscle strength, exercise tolerance and physical performance.
- The study tested UA in 500mg and 1000 mg doses against placebo in a 3-arm randomized-controlled trial in n= 88 subjects aged 40-64y who were healthy, overweight (BMI 25.0-34.9 kg/m2), sedentary, and who had a low VO2max at study inclusion. 79 subjects completed the study.
- Subjects were assessed at baseline, midpoint (2 months) and endpoint (4 months). In addition to the UA intervention, subjects were asked to maintain low physical activity status for the duration of the trial, and avoid pomegranates and supplements known to influence muscle performance (high protein, CoQ10m vitamin B3 or L-carnitine).
- Though a difference in peak power output (primary outcome) was not observed, muscle strength improved by up to c. 12% with 500 mg daily UA (p=0.027). With 1000 mg UA daily, aerobic endurance improved by up to 15% (p=0.03), gait speed increased by 7% (p=0.004), and in the 6-minute walk test subjects improved by 7% (p=0.008) and walked on average more than 30 additional meters, indicating a clinically meaningful difference in mobility.
- In addition, subjects in the UA groups had improved biomarkers of cellular health. With 1000 mg UA daily, inflammation was reduced (CRP, p<0.05; IFN-γ and TNF-α, both p<0.05). In addition, biomarkers of mitochondrial efficiency were also improved with 500 mg UA daily, Iing increased protein levels related to improved mitophagy, and expression of genes belonging to mitochondria.
- UA was deemed as safe and well tolerated at both 500 mg and 1000 mg doses for 4 months’ administration.
- A strength of the study was that the groups were balanced for all physiological parameters at baseline. However, the ratio of females was 2:1, and ethnicity was mainly western European. This may limit interpretation of the findings.
- All authors except one are either employees, board members or members of the scientific advisory board of Amazentis SA, who both manufacture Mitopure, the UA supplement used, and who funded this trial.
Clinical practice applications:
- Mitophagy is an important step in improving mitochondrial health. This study demonstrates the potential of UA to activate this pathway.
- In healthy middle-aged adults who are overweight or obese, sedentary and with low physical performance, oral UA supplementation at a sufficient dose and duration may:
- increase muscle strength
- increase mitophagy proteins in human skeletal muscle, as well as various other mitochondrial markers
- increase exercise performance and aerobic exercise
- be a valuable intervention to consider in clients who are suffering from mitochondrial dysfunction
Considerations for future research:
- This study was exploratory and the sample size for some of the outcomes was very small and inadequate to demonstrate true statistical significance. Future studies of similar design are needed to confirm the findings
- Nevertheless, the study was well-structured with carefully elaborated markers. It could be used as a template for future studies.
Abstract
Targeting mitophagy to activate the recycling of faulty mitochondria during aging is a strategy to mitigate muscle decline. We present results from a randomized, placebo-controlled trial in middle-aged adults where we administer a postbiotic compound Urolithin A (Mitopure), a known mitophagy activator, at two doses for 4 months (NCT03464500). The data show significant improvements in muscle strength (∼12%) with intake of Urolithin A. We observe clinically meaningful improvements with Urolithin A on aerobic endurance (peak oxygen oxygen consumption [VO2]) and physical performance (6 min walk test) but do not notice a significant improvement on peak power output (primary endpoint). Levels of plasma acylcarnitines and C-reactive proteins are significantly lower with Urolithin A, indicating higher mitochondrial efficiency and reduced inflammation. We also examine expression of proteins linked to mitophagy and mitochondrial metabolism in skeletal muscle and find a significant increase with Urolithin A administration. This study highlights the benefit of Urolithin A to improve muscle performance.
-
4.
Lipids activate skeletal muscle mitochondrial fission and quality control networks to induce insulin resistance in humans.
Axelrod, CL, Fealy, CE, Erickson, ML, Davuluri, G, Fujioka, H, Dantas, WS, Huang, E, Pergola, K, Mey, JT, King, WT, et al
Metabolism: clinical and experimental. 2021;121:154803
-
-
-
Free full text
-
Plain language summary
Insulin resistance is a key pathophysiological mechanism in the development and progression of type 2 diabetes. Abnormalities in lipid metabolism and ectopic lipid accumulation are known to directly contribute to the onset of insulin resistance. Authors hypothesised that lipid infusion would increase dynamin related protein 1 [a type of protein]-mediated mitochondrial fission in skeletal muscle independent of function and content, consequently reducing peripheral insulin sensitivity. The study included sedentary but otherwise healthy adults who were prospectively randomized to receive either lipid or saline infusion to isolate the direct contribution of fatty acids to skeletal muscle mitochondrial dynamics. Results show that mitochondrial fission and quality control networks are activated in response to lipid infusion which occurs independent of changes in mitochondrial content or capacity and contributes to the onset of insulin resistance in healthy humans. Authors conclude that treatments that limit lipid-induced activation of mitochondrial fission and/or quality control processes may have therapeutic value in the treatment of insulin resistance.
Abstract
BACKGROUND AND AIMS A diminution in skeletal muscle mitochondrial function due to ectopic lipid accumulation and excess nutrient intake is thought to contribute to insulin resistance and the development of type 2 diabetes. However, the functional integrity of mitochondria in insulin-resistant skeletal muscle remains highly controversial. METHODS 19 healthy adults (age:28.4 ± 1.7 years; BMI:22.7 ± 0.3 kg/m2) received an overnight intravenous infusion of lipid (20% Intralipid) or saline followed by a hyperinsulinemic-euglycemic clamp to assess insulin sensitivity using a randomized crossover design. Skeletal muscle biopsies were obtained after the overnight lipid infusion to evaluate activation of mitochondrial dynamics proteins, ex-vivo mitochondrial membrane potential, ex-vivo oxidative phosphorylation and electron transfer capacity, and mitochondrial ultrastructure. RESULTS Overnight lipid infusion increased dynamin related protein 1 (DRP1) phosphorylation at serine 616 and PTEN-induced kinase 1 (PINK1) expression (P = 0.003 and P = 0.008, respectively) in skeletal muscle while reducing mitochondrial membrane potential (P = 0.042). The lipid infusion also increased mitochondrial-associated lipid droplet formation (P = 0.011), the number of dilated cristae, and the presence of autophagic vesicles without altering mitochondrial number or respiratory capacity. Additionally, lipid infusion suppressed peripheral glucose disposal (P = 0.004) and hepatic insulin sensitivity (P = 0.014). CONCLUSIONS These findings indicate that activation of mitochondrial fission and quality control occur early in the onset of insulin resistance in human skeletal muscle. Targeting mitochondrial dynamics and quality control represents a promising new pharmacological approach for treating insulin resistance and type 2 diabetes. CLINICAL TRIAL REGISTRATION NCT02697201, ClinicalTrials.gov.
-
5.
NAD+-Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial Function or Skeletal Muscle Function in Physically Compromised Older Adults.
Connell, NJ, Grevendonk, L, Fealy, CE, Moonen-Kornips, E, Bruls, YMH, Schrauwen-Hinderling, VB, de Vogel, J, Hageman, R, Geurts, J, Zapata-Perez, R, et al
The Journal of nutrition. 2021;151(10):2917-2931
-
-
-
Free full text
-
Plain language summary
Ageing is associated with the progressive loss of muscle, which can result in impaired movement, an increased risk for falls and disrupted energy production. During ageing there is a decrease in one of the substrates involved in producing energy known as NAD+. Studies in animals have shown that supplementing with a precursor of NAD+ promotes longevity and energy production. In humans supplementation with a precursor of NAD+ has been shown to improve heart health and be of benefit to individuals with obesity. This randomised control trial aimed to determine the effect of supplementing the NAD+ precursors, tryptophan, nicotinic acid, and nicotinamide on muscle function in 14 older adults with impaired physical function. The results showed that supplementation had no effect on NAD+ and had no effect on muscular energy production nor exercise performance following a cycling test. It was concluded that supplementation with an NAD+ precursor does not improve muscle function. This study could be used by healthcare professionals to understand that a combination supplement of tryptophan, nicotinic acid, and nicotinamide may not benefit the physical function of older adults.
Abstract
BACKGROUND Boosting NAD+ via supplementation with niacin equivalents has been proposed as a potential modality capable of promoting healthy aging and negating age-dependent declines of skeletal muscle mass and function. OBJECTIVES We investigated the efficacy of NAD+-precursor supplementation (tryptophan, nicotinic acid, and nicotinamide) on skeletal muscle mitochondrial function in physically compromised older adults. METHODS A randomized, double-blind, controlled trial was conducted in 14 (female/male: 4/10) community-dwelling, older adults with impaired physical function [age, 72.9 ± 4.0 years; BMI, 25.2 ± 2.3 kg/m2]. Participants were supplemented with 207.5 mg niacin equivalents/day [intervention (INT)] and a control product (CON) that did not contain niacin equivalents, each for 32 days. The primary outcomes tested were mitochondrial oxidative capacity and exercise efficiency, analyzed by means of paired Student's t-tests. Secondary outcomes, such as NAD+ concentrations, were analyzed accordingly. RESULTS Following supplementation, skeletal muscle NAD+ concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD+-precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD+ metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT, 103.4 ± 30.7 compared with CON, 108.7 ± 33.4; P = 0.495] improved under NAD+-precursor supplementation, nor did net exercise efficiency during the submaximal cycling test [INT, 20.2 ± 2.77 compared with CON, 20.8 ± 2.88; P = 0.342]. CONCLUSIONS Our findings are consistent with previous findings on NAD+ efficacy in humans, and we show in community-dwelling, older adults with impaired physical function that NAD+-precursor supplementation through L-tryptophan, nicotinic acid, and nicotinamide does not improve mitochondrial or skeletal muscle function. This study was registered at clinicaltrials.gov as NCT03310034.
-
6.
A Single Bout of Premeal Resistance Exercise Improves Postprandial Glucose Metabolism in Obese Men with Prediabetes.
Bittel, AJ, Bittel, DC, Mittendorfer, B, Patterson, BW, Okunade, AL, Abumrad, NA, Reeds, DN, Cade, WT
Medicine and science in sports and exercise. 2021;53(4):694-703
-
-
-
Free full text
-
Plain language summary
Prediabetes is a metabolic condition defined by elevated fasting (impaired fasting glucose) and/or postprandial (impaired glucose tolerance) plasma glucose. The aim of this study was to determine the effects of a single bout of resistance exercise on postprandial glucose metabolism following a mixed meal in obese, sedentary men with prediabetes. This study is a randomised, cross-over study design which enrolled ten participants. Participants were aged 39-62 years, obese, and demonstrated insulin resistance with compensatory increases in beta cell function. Results show that a single bout of resistance exercise performed 4.5 hours before a mixed meal (as opposed to an oral glucose tolerance test) reduced total postprandial glucose appearance, increased insulin sensitivity, and reduced the glycaemic response to a mixed meal. However, it did not have effect on glucose oxidation in obese men with prediabetes. Improvements in insulin sensitivity were complemented by reduced postprandial insulin concentration. Authors conclude that further investigation is needed to elucidate how resistance exercise affects exogenous (meal) vs endogenous postprandial glucose metabolism, and if additional bouts of exercise (i.e. training) produce superior outcomes for this population.
Abstract
INTRODUCTION Prediabetes is a major risk factor for type 2 diabetes and cardiovascular diseases. Although resistance exercise (RE) is recommended for individuals with prediabetes, the effects of RE on postprandial glucose metabolism in this population are poorly understood. Therefore, the purpose of this study was to elucidate how RE affects postprandial glucose kinetics, insulin sensitivity, beta cell function, and glucose oxidation during the subsequent meal in sedentary men with obesity and prediabetes. METHODS We studied 10 sedentary men with obesity (body mass index, 33 ± 3 kg·m-2) and prediabetes by using a randomized, cross-over study design. After an overnight fast, participants completed either a single bout of whole-body RE (seven exercises, 3 sets of 10-12 repetitions at 80% one-repetition maximum each) or an equivalent period of rest. Participants subsequently completed a mixed meal test in conjunction with an intravenous [6,6-2H2]glucose infusion to determine basal and postprandial glucose rate of appearance (Ra) and disappearance (Rd) from plasma, insulin sensitivity, and the insulinogenic index (a measure of beta cell function). Skeletal muscle biopsies were obtained 90 min postmeal to evaluate pyruvate-supported and maximal mitochondrial respiration. Whole-body carbohydrate oxidation was assessed using indirect calorimetry. RESULTS RE significantly reduced the postprandial rise in glucose Ra and plasma glucose concentration. Postprandial insulin sensitivity was significantly greater after RE, whereas postprandial plasma insulin concentration was significantly reduced. RE had no effect on the insulinogenic index, postprandial pyruvate respiration, or carbohydrate oxidation. CONCLUSION/INTERPRETATION A single bout of RE has beneficial effects on postprandial glucose metabolism in men with obesity and prediabetes by increasing postprandial insulin sensitivity, reducing the postprandial rise in glucose Ra, and reducing postprandial plasma insulin concentration.
-
7.
Randomized trial of weight loss in primary breast cancer: Impact on body composition, circulating biomarkers and tumor characteristics.
Demark-Wahnefried, W, Rogers, LQ, Gibson, JT, Harada, S, Frugé, AD, Oster, RA, Grizzle, WE, Norian, LA, Yang, ES, Della Manna, D, et al
International journal of cancer. 2020;146(10):2784-2796
-
-
-
Free full text
-
Plain language summary
Obesity directly impacts survival in individuals with breast cancer. Previous studies in animals and at the cellular level have shown that calorie restriction and increased physical activity to achieve a negative energy balance may inhibit cancer progression, however effects in patients are unknown. This randomised control trial aimed to determine the impact of a pre surgery weight loss programme in 32 women with breast cancer on tumour biology and other markers of disease. The results were mixed and showed that proteins which bind to hormones involved in breast cancer were increased, which could decrease severity of disease. However, tumour biology was negatively affected; specific genes involved in breast cancer progression were increased and those involved in tumour suppression were decreased. Although this did result in no net effect on the rate at which new tumours were formed. It was concluded that although the study showed mixed results, ultimately the rate at which new tumours were formed remained unaffected. This trial could be used by healthcare professionals to understand that the role of negative energy intake in breast cancer development is complicated and warrants further research.
Abstract
Obesity adversely impacts overall and cancer-specific survival among breast cancer patients. Preclinical studies demonstrate negative energy balance inhibits cancer progression; however, feasibility and effects in patients are unknown. A two-arm, single-blinded, randomized controlled weight-loss trial was undertaken presurgery among 32 overweight/obese, Stage 0-II breast cancer patients. The attention control arm (AC) received basic nutritional counseling and upper-body progressive resistance training whereas the weight loss intervention (WLI) arm received identical guidance, plus counseling on caloric restriction and aerobic exercise to promote 0.68-0.92 kg/week weight loss. Anthropometrics, body composition, blood and survey data were collected at baseline and presurgery ∼30 days later. Tumor markers (e.g., Ki67) and gene expression were assessed on biopsy and surgical specimens; sera were analyzed for cytokines, growth and metabolic factors. Significant WLI vs. AC differences were seen in baseline-to-follow-up changes in weight (-3.62 vs. -0.52 kg), %body fat (-1.3 vs. 0%), moderate-to-vigorous physical activity (+224 vs. +115 min/week), caloric density (-0.3 vs. 0 kcal/g), serum leptin (-12.3 vs. -4.0 ng/dl) and upregulation of tumor PI3Kinase signaling and cell cycle-apoptosis related genes (CC-ARG; all p-values <0.05). Cytolytic CD56dim NK cell expression was positively associated with weight loss; CC-ARG increased with physical activity. Increased tumor (nuclear) TNFα and IL-1β, CX3CL1 and CXCL1 gene expression was observed in the WLI. Tumor Ki67 did not differ between arms. Feasibility benchmarks included 80% accrual, 100% retention, no adverse effects and excellent adherence. Short-term weight loss interventions are feasible; however, mixed effects on tumor biology suggest unclear benefit to presurgical caloric restriction, but possible benefits of physical activity.
-
8.
Lipid Metabolism Links Nutrient-Exercise Timing to Insulin Sensitivity in Men Classified as Overweight or Obese.
Edinburgh, RM, Bradley, HE, Abdullah, NF, Robinson, SL, Chrzanowski-Smith, OJ, Walhin, JP, Joanisse, S, Manolopoulos, KN, Philp, A, Hengist, A, et al
The Journal of clinical endocrinology and metabolism. 2020;105(3)
-
-
-
Free full text
-
Plain language summary
Following exercise, various metabolic changes occur which may be of benefit in fighting diseases such as type 2 diabetes and obesity. However, the degree of change may vary depending on whether the exercise has been performed pre or post meal consumption. This 6-week randomised crossover trial of 30 overweight or obese men aimed to determine the effect of exercising before or after breakfast on the use of fats and sugars by the body. The results showed that exercise before breakfast increased fat and sugar use in the body and also resulted in the alteration of eight genes associated with metabolism. Exercise before carbohydrate consumption also increased lipid use and improved insulin sensitivity, however body composition was similar regardless of when exercise was performed. It was concluded that exercising in the fasted state can optimise the body’s response without having to change intensity or effort. This study could be used by health care professionals to advise patients with obesity or overweight that exercising whilst in the fasted state could optimise their outcomes without having to increase exercise intensity or frequency.
Abstract
CONTEXT Pre-exercise nutrient availability alters acute metabolic responses to exercise, which could modulate training responsiveness. OBJECTIVE To assess acute and chronic effects of exercise performed before versus after nutrient ingestion on whole-body and intramuscular lipid utilization and postprandial glucose metabolism. DESIGN (1) Acute, randomized, crossover design (Acute Study); (2) 6-week, randomized, controlled design (Training Study). SETTING General community. PARTICIPANTS Men with overweight/obesity (mean ± standard deviation, body mass index: 30.2 ± 3.5 kg⋅m-2 for Acute Study, 30.9 ± 4.5 kg⋅m-2 for Training Study). INTERVENTIONS Moderate-intensity cycling performed before versus after mixed-macronutrient breakfast (Acute Study) or carbohydrate (Training Study) ingestion. RESULTS Acute Study-exercise before versus after breakfast consumption increased net intramuscular lipid utilization in type I (net change: -3.44 ± 2.63% versus 1.44 ± 4.18% area lipid staining, P < 0.01) and type II fibers (-1.89 ± 2.48% versus 1.83 ± 1.92% area lipid staining, P < 0.05). Training Study-postprandial glycemia was not differentially affected by 6 weeks of exercise training performed before versus after carbohydrate intake (P > 0.05). However, postprandial insulinemia was reduced with exercise training performed before but not after carbohydrate ingestion (P = 0.03). This resulted in increased oral glucose insulin sensitivity (25 ± 38 vs -21 ± 32 mL⋅min-1⋅m-2; P = 0.01), associated with increased lipid utilization during exercise (r = 0.50, P = 0.02). Regular exercise before nutrient provision also augmented remodeling of skeletal muscle phospholipids and protein content of the glucose transport protein GLUT4 (P < 0.05). CONCLUSIONS Experiments investigating exercise training and metabolic health should consider nutrient-exercise timing, and exercise performed before versus after nutrient intake (ie, in the fasted state) may exert beneficial effects on lipid utilization and reduce postprandial insulinemia.
-
9.
Metabolic impact of weight loss induced reduction of adipose ACE-2 - Potential implication in COVID-19 infections?
Li, L, Spranger, L, Soll, D, Beer, F, Brachs, M, Spranger, J, Mai, K
Metabolism: clinical and experimental. 2020;113:154401
-
-
-
Free full text
-
Plain language summary
Obesity is now recognised as a risk factor for increased severity of Covid-19 infections. ACE-2 is a protein that has many functions but also allows Covid-19 into cells and is particularly evident in body tissues, which store fat. It is therefore possible that Covid-19 will target fat-storing tissues in the body. This 12-month randomised control weight-loss intervention study of 143 obese individuals aimed to determine ACE-2 expression and whether it could be modified by weight loss. The results showed that ACE-2 was only present in fat storing tissue and not muscle tissue. Interestingly individuals with pre-diabetes or diabetes had the lowest levels of ACE-2. Weight loss resulted in reduced ACE-2 in fat storing tissue, which resulted in an improvement in markers for diabetes. It was concluded that reduction of ACE-2 in fat storing tissues as a result of weight loss can improve markers for diabetes and could impact the severity of Covid-19 infection. Healthcare professionals could use this study to understand how weight loss in patients with obesity could decrease their risk of severe Covid-19 infection.
Abstract
BACKGROUND & AIMS Angiotensin converting enzyme (ACE)-2 is a modulator of adipose tissue metabolism. However, human data of adipose ACE-2 is rarely available. Considering that, ACE-2 is believed to be the receptor responsible for cell entry of SARS-CoV-2, a better understanding of its regulation is desirable. We therefore characterized the modulation of subcutaneous adipose ACE-2 mRNA expression during weight loss and the impact of ACE-2 expression on weight loss induced short- and long-term improvements of glucose metabolism. METHODS 143 subjects (age > 18; BMI ≥ 27 kg/m2) were analyzed before and after a standardized 12-week dietary weight reduction program. Afterwards subjects were randomized to a 12-month lifestyle intervention or a control group (Maintain-Adults trial). Insulin sensitivity (IS) was estimated by HOMA-IR (as an estimate of liver IS) and ISIClamp (as an estimate of skeletal muscle IS). ACE-2 mRNA expression (ACE-2AT) was measured in subcutaneous adipose tissue before and after weight loss. RESULTS ACE-2AT was not affected by obesity, but was reduced in insulin resistant subjects. Weight loss resulted in a decline of ACE-2AT (29.0 (20.0-47.9) vs. 21.0 (13.0-31.0); p = 1.6 ∗ 10-7). A smaller reduction of ACE-2 AT (ΔACE-2AT) was associated with a larger improvement of ISIClamp (p = 0.013) during weight reduction over 3 months, but not with the extend of weight loss. The degree of changes in insulin resistance were preserved until month 12 and was also predicted by the weight loss induced degree of ΔACE-2AT (p = 0.011). CONCLUSIONS Our data indicate that subcutaneous adipose ACE-2 expression correlates with insulin sensitivity. Weight loss induced decline of subcutaneous adipose ACE-2 expression might affect short- and long-term improvement of myocellular insulin sensitivity, which might be also relevant in the context of ACE-2 downregulation by SARS-CoV-2. TRIAL REGISTRATION ClinicalTrials.gov number: NCT00850629, https://clinicaltrials.gov/ct2/show/NCT00850629, date of registration: February 25, 2009.
-
10.
Effect of inorganic nitrate on exercise capacity, mitochondria respiration, and vascular function in heart failure with reduced ejection fraction.
Woessner, MN, Neil, C, Saner, NJ, Goodman, CA, McIlvenna, LC, Ortiz de Zevallos, J, Garnham, A, Levinger, I, Allen, JD
Journal of applied physiology (Bethesda, Md. : 1985). 2020;128(5):1355-1364
-
-
-
Free full text
Plain language summary
Patients with chronic heart failure (CHF) are characterised by reduced aerobic capacity (V ̇O2peak) and early fatigue. Improving V ̇O2peak is an important clinical goal in CHF as it is correlated with reduced mortality rate and increased quality of life. The main aim of this study was to test the hypothesis that chronic oral inorganic nitrate supplementation will improve V ̇O2peak during treadmill exercise in patients with heart failure with reduced ejection fraction (HFrEF). This study is a randomised, placebo-controlled, double-blind, crossover study. Nineteen participants were recruited, and 16 individuals with diagnosed HFrEF completed the study. Participants were randomised to consume either nitrate-rich beetroot juice (210 mL, 16 mmol nitrate) or a nitrate-depleted placebo for 5 days. Results show that in patients with HFrEF, chronic oral inorganic nitrate supplementation had no significant effect on aerobic exercise capacity, vascular function, peripheral and central blood pressures, or muscle respiration. Authors conclude that future studies should characterise the diversity and abundance of the oral microbiome in HFrEF to elucidate approaches that could lead to a potential benefit of oral nitrate supplementation.
Abstract
Chronic underperfusion of the skeletal muscle tissues is a contributor to a decrease in exercise capacity in patients with heart failure with reduced ejection fraction (HFrEF). This underperfusion is due, at least in part, to impaired nitric oxide (NO) bioavailability. Oral inorganic nitrate supplementation increases NO bioavailability and may be used to improve exercise capacity, vascular function, and mitochondrial respiration. Sixteen patients with HFrEF (fifteen men, 63 ± 4 yr, body mass index: 31.8 ± 2.1 kg/m2) participated in a randomized, double-blind, crossover design study. Following consumption of either nitrate-rich beetroot juice (16 mmol nitrate/day) or a nitrate-depleted placebo for 5 days, participants completed separate visits for assessment of exercise capacity, endothelial function, and muscle mitochondrial respiration. Participants then had a 2-wk washout before completion of the same protocol with the other intervention. Statistical significance was set a priori at P < 0.05, and between-treatment differences were analyzed via paired t test analysis. Following nitrate supplementation, both plasma nitrate and nitrite increased (933%, P < 0.001 and 94%, P < 0.05, respectively). No differences were observed for peak oxygen consumption (nitrate: 18.5 ± 1.4 mL·kg-1·min-1, placebo: 19.3 ± 1.4 mL·kg-1·min-1; P = 0.13) or time to exhaustion (nitrate: 1,165 ± 92 s, placebo: 1,207 ± 96 s; P = 0.16) following supplementation. There were no differences between interventions for measures of vascular function, mitochondrial respiratory function, or protein expression (all P > 0.05). Inorganic nitrate supplementation did not improve exercise capacity and skeletal muscle mitochondrial respiratory function in HFrEF. Future studies should explore alternative interventions to improve peripheral muscle tissue function in HFrEF.NEW & NOTEWORTHY This is the largest study to date to examine the effects of inorganic nitrate supplementation in patients with heart failure with reduced ejection fraction (HFrEF) and the first to include measures of vascular function and mitochondrial respiration. Although daily supplementation increased plasma nitrite, our data indicate that supplementation with inorganic nitrate as a standalone treatment is ineffective at improving exercise capacity, vascular function, or mitochondrial respiration in patients with HFrEF.