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It is well known that a training intervention leads to mitochondrial adaptations with increased skeletal muscle mitochondrial biogenesis and function. Studies have recently indicated that skeletal muscle mitochondrial function is important for athletic performance. During exercise reactive oxygen species are released from skeletal muscle potentially leading to adaptations but maybe also to fatigue. Focus has been on how chronic antioxidant supplementation affects a training adaptation, where some studies are reporting an abolished adaptation. Whether acute antioxidant supplementation could have a positive effect on fatigue and performance is interesting and highly relevant in sports where athletes are competing over several consecutive days or on the same day, with preliminary competitions in the morning and finals in the afternoon, where it is important for the athletes to recover fast. This review provides an overview of the effects of acute antioxidant supplementation and whether it leads to improved performance and/or faster recovery in humans.
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AIM: High-resolution respirometry in human permeabilized muscle fibers is extensively used for analysis of mitochondrial adaptions to nutrition and exercise interventions, and is linked to athletic performance. However, the lack of standardization of experimental conditions limits quantitative inter- and intra-laboratory comparisons. METHODS: In our study, an international team of investigators measured mitochondrial respiration of permeabilized muscle fibers obtained from three biopsies (vastus lateralis) from the same healthy volunteer to avoid inter-individual variability. High-resolution respirometry assays were performed together at the same laboratory to assess whether the heterogenity in published results are due to the effects of respiration media (MiR05 versus Z) with or without the myosin inhibitor blebbistatin at low- and high-oxygen regimes. RESULTS: Our findings reveal significant differences between respiration media for OXPHOS and ETcapacities supported by NADH&succinate-linked substrates at different oxygen concentrations. Respiratory capacities were approximately 1.5-fold higher in MiR05 at high-oxygen regimes compared to medium Z near air saturation. The presence or absence of blebbistatin in human permeabilized muscle fiber preparations was without effect on oxygen flux. CONCLUSION: Our study constitutes a basis to harmonize and establish optimum experimental conditions for respirometric studies of permeabilized human skeletal muscle fibers to improve reproducibility.
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Adipose tissues, particularly beige and brown adipose tissue, play crucial roles in energy metabolism. Brown adipose tissues' thermogenic capacity and the appearance of beige cells within white adipose tissue have spurred interest in their metabolic impact and therapeutic potential. Brown and beige fat cells, activated by environmental factors like cold exposure or by pharmacology, share metabolic mechanisms that drive non-shivering thermogenesis. Understanding these two cell types requires advanced, yet broadly applicable in vitro models that reflect the complex microenvironment and vasculature of adipose tissues. Here we present mouse vascularized adipose spheroids of the stromal vascular microenvironment from inguinal white adipose tissue, a tissue with 'beiging' capacity in mice and humans. We show that adding a scaffold improves vascular sprouting, enhances spheroid growth, and upregulates adipogenic markers, thus reflecting increased adipocyte maturity. Transcriptional profiling via RNA sequencing revealed distinct metabolic pathways upregulated in our vascularized adipose spheroids, with increased expression of genes involved in glucose metabolism, lipid metabolism, and thermogenesis. Functional assessment demonstrated increased oxygen consumption in vascularized adipose spheroids compared to classical 2D cultures, which was enhanced by ß-adrenergic receptor stimulation correlating with elevated ß-adrenergic receptor expression. Moreover, stimulation with the naturally occurring adipokine, FGF21, induced Ucp1 mRNA expression in the vascularized adipose spheroids. In conclusion, vascularized inguinal white adipose tissue spheroids provide a physiologically relevant platform to study how the stromal vascular microenvironment shapes adipocyte responses and influence activated thermogenesis in beige adipocytes.
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Esferoides Celulares , Termogênese , Animais , Camundongos , Esferoides Celulares/metabolismo , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/citologia , Camundongos Endogâmicos C57BL , Masculino , Adipócitos/metabolismo , Adipócitos/citologia , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/citologia , Células Cultivadas , Adipócitos Bege/metabolismo , Adipócitos Bege/citologia , Metabolismo Energético , Adipogenia/fisiologia , Sistemas MicrofisiológicosRESUMO
BACKGROUND AND OBJECTIVES: Dual amylin and calcitonin receptor agonists (DACRAs) are therapeutic candidates in the treatment of obesity with beneficial effects on weight loss superior to suppression of food intake. Hence, suggesting effects on energy expenditure by possibly targeting mitochondria in metabolically active tissue. METHODS: Male rats with HFD-induced obesity received a DACRA, KBP-336, every third day for 8 weeks. Upon study end, mitochondrial respiratory capacity (MRC), - enzyme activity, - transcriptional factors, and -content were measured in perirenal (pAT) and inguinal adipose tissue. A pair-fed group was included to examine food intake-independent effects of KBP-336. RESULTS: A vehicle-corrected weight loss (23.4 ± 2.8%) was achieved with KBP-336, which was not observed to the same extent with the food-restricted weight loss (12.4 ± 2.8%) (P < 0.001). Maximal coupled respiration supported by carbohydrate and lipid-linked substrates was increased after KBP-336 treatment independent of food intake in pAT (P < 0.01). Moreover, oligomycin-induced leak respiration and the activity of citrate synthase and ß-hydroxyacetyl-CoA-dehydrogenase were increased with KBP-336 treatment (P < 0.05). These effects occurred without changes in mitochondrial content in pAT. CONCLUSIONS: These findings demonstrate favorable effects of KBP-336 on MRC in adipose tissue, indicating an increased energy expenditure and capacity to utilize fatty acids. Thus, providing more mechanistic insight into the DACRA-induced weight loss.
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High-resolution respirometry (HRR) can assess peripheral blood mononuclear cell (PBMC) bioenergetics, but no standardized medium for PBMC preparation and HRR analysis exist. Here, we study the effect of four different media (MiR05, PBS, RPMI, Plasmax) on the count, size, and HRR (Oxygraph-O2k) of intact PBMCs. Remarkably, the cell count was 21 % higher when PBMCs were resuspended in MiR05 than in PBS or Plasmax, causing O2 flux underestimation during HRR due to inherent adjustments. Moreover, smaller cell size and cell aggregation was observed in MiR05. Based on our findings, we propose that Plasmax, PBS or RPMI is more suitable than MiR05 for HRR of intact PBMCs. We provide oxygen solubility factors for Plasmax and PBS and encourage further optimization of a standardized HRR protocol for intact PBMCs.
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Tamanho Celular , Meios de Cultura , Leucócitos Mononucleares , Leucócitos Mononucleares/metabolismo , Humanos , Meios de Cultura/química , Respiração CelularRESUMO
INTRODUCTION: Liver fat (LF) and visceral adipose tissue (VAT) content decreases with training, however, this has mainly been investigated in sedentary obese or healthy participants. The aim of this study was to investigate the effects of repeated prolonged exercise on LF and VAT content in well-trained older men and to compare baseline LF and VAT content to recreationally active older men. METHOD: A group of five well-trained older men were tested before and after cycling a total distance of 2558 km in 16 consecutive days. VAT content and body composition was measured using DXA before a bicycle ergometer test was performed to determine maximal fat oxidation (MFO), maximal oxygen consumption ( VO 2 max $$ {\mathrm{VO}}_{2_{\mathrm{max}}} $$ ), and the relative intensity at which MFO occurred (Fatmax). LF content was measured on a separate day using MRI. For comparison of baseline values, a control group of eight healthy age- and BMI-matched recreationally active men were recruited. RESULTS: The well-trained older men had lower VAT (p = 0.02), and a tendency toward lower LF content (p = 0.06) compared with the control group. The intervention resulted in decreased LF content (p = 0.02), but VAT, fat mass, and lean mass remained unchanged. VO 2 max $$ {\mathrm{VO}}_{2_{\mathrm{max}}} $$ , MFO, and Fatmax were not affected by the intervention. CONCLUSION: The study found that repeated prolonged exercise reduced LF content, but VAT and VO 2 max $$ {\mathrm{VO}}_{2_{\mathrm{max}}} $$ remained unchanged. Aerobic capacity was aligned with lower LF and VAT in older active men.
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Exercício Físico , Gordura Intra-Abdominal , Masculino , Humanos , Idoso , Obesidade/metabolismo , Fígado/diagnóstico por imagem , Teste de Esforço , Tecido Adiposo/metabolismo , Consumo de OxigênioRESUMO
BACKGROUND: Hepatocellular senescence may be a causal factor in the development and progression of non-alcoholic steatohepatitis (NASH). The most effective currently available treatment for NASH is lifestyle intervention, including dietary modification. This study aimed to evaluate the effects of dietary intervention on hallmarks of NASH and molecular signatures of hepatocellular senescence in the Gubra-Amylin NASH (GAN) diet-induced obese (DIO) and biopsy-confirmed mouse model of NASH. METHODS: GAN DIO-NASH mice with liver biopsy-confirmed NASH and fibrosis received dietary intervention by switching to chow feeding (chow reversal) for 8, 16 or 24 weeks. Untreated GAN DIO-NASH mice and chow-fed C57BL/6J mice served as controls. Pre-to-post liver biopsy histology was performed for within-subject evaluation of NAFLD Activity Score and fibrosis stage. Terminal endpoints included blood/liver biochemistry, quantitative liver histology, mitochondrial respiration and RNA sequencing. RESULTS: Chow-reversal promoted substantial benefits on metabolic outcomes and liver histology, as demonstrated by robust weight loss, complete resolution of hepatomegaly, hypercholesterolemia, elevated transaminase levels and hepatic steatosis in addition to attenuation of inflammatory markers. Notably, all DIO-NASH mice demonstrated ≥ 2 point significant improvement in NAFLD Activity Score following dietary intervention. While not improving fibrosis stage, chow-reversal reduced quantitative fibrosis markers (PSR, collagen 1a1, α-SMA), concurrent with improved liver mitochondrial respiration, complete reversal of p21 overexpression, lowered γ-H2AX levels and widespread suppression of gene expression markers of hepatocellular senescence. CONCLUSIONS: Dietary intervention (chow reversal) substantially improves metabolic, biochemical and histological hallmarks of NASH and fibrosis in GAN DIO-NASH mice. These benefits were reflected by progressive clearance of senescent hepatocellular cells, making the model suitable for profiling potential senotherapeutics in preclinical drug discovery for NASH.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/patologia , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Dieta Hiperlipídica/efeitos adversos , Camundongos Endogâmicos C57BL , Fígado/patologia , Obesidade/metabolismo , Cirrose Hepática/patologia , Modelos Animais de Doenças , BiópsiaRESUMO
BACKGROUND: The aim of this study was to investigate the effect of prolonged endurance exercise on adipose tissue inflammation markers and mitochondrial respiration in younger and older men. METHODS: "Young" (aged 30 years, n = 7) and "old" (aged 65 years, n = 7) trained men were exposed to an exercise intervention of 15 consecutive days biking 7 to 9 hours/day at 63% and 65% of maximal heart rate (young and old, respectively), going from Copenhagen, Denmark to Palermo, Italy. Adipose tissue was sampled from both the gluteal and abdominal depot before and after the intervention. Mitochondrial respiration was measured by high-resolution respirometry, and adipose inflammation was assessed by immunohistochemical staining of paraffin embedded sections. RESULTS: An increased number of CD163+ macrophages was observed in both the gluteal and abdominal depot (P < .01). In addition, an increased mitochondrial respiration was observed in the abdominal adipose tissue from men in the young group with complex I (CIp) stimulated respiration, complex I + II (CI+IIp) stimulated respiration and the capacity of the electron transport system (ETS) (P < .05), and in the older group an increase in CIp and CI+IIp stimulated respiration (P < .05) was found. CONCLUSION: Overall, we found a positive effect of prolonged endurance exercise on adipose tissue inflammation markers and mitochondrial respiration in both young and old trained men, and no sign of attenuated function in adipose tissue with age.
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Tecido Adiposo , Respiração , Masculino , Humanos , Idoso , Terapia por Exercício , Macrófagos , InflamaçãoRESUMO
Insulin deficiency in type 1 diabetes (T1D) leads to an impairment of glucose metabolism and mitochondrial function. Actovegin is a hemodialysate of calf blood, which has been shown to enhance glucose uptake and cell metabolism in healthy human skeletal muscle. The objectives of this study were to determine the effects of Actovegin on skeletal muscle mitochondrial respiration and functional aerobic capacity in a T1D mouse model. Effects on the expression of mitochondrial proteins, body mass, and food and water consumption were also investigated. Streptozotocin-induced T1D male C57B1/6 mice (aged 3-4 months) were randomized to an Actovegin group and a control group. Every third day, the Actovegin and control groups were injected intraperitoneally with (0.1 mL) Actovegin and (0.1 mL) physiological salt solution, respectively. Oxidative phosphorylation (OXPHOS) capacity of the vastus lateralis muscle was measured by high resolution respirometry in addition to the expression levels of the mitochondrial complexes as well as voltage-dependent anion channel. Functional aerobic capacity was measured using a rodent treadmill protocol. Body mass and food and water consumption were also measured. After 13 days, in comparison to the control group, the Actovegin group demonstrated a significantly higher skeletal muscle mitochondrial respiratory capacity in an ADP-restricted and ADP-stimulated environment. The Actovegin group displayed a significantly lesser decline in functional aerobic capacity and baseline body mass after 13 days. There were no significant differences in food or water consumption between groups. Actovegin could act as an effective agent for facilitating glucose metabolism and improving OXPHOS capacity and functional aerobic capacity in T1D. Further investigation is warranted to establish Actovegin's potential as an alternative therapeutic drug for T1D.
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Diabetes Mellitus Tipo 1 , Heme/análogos & derivados , Masculino , Camundongos , Humanos , Animais , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Modelos Animais de Doenças , Músculo Esquelético/metabolismo , Mitocôndrias/metabolismo , Respiração , Glucose/metabolismo , Mitocôndrias Musculares/metabolismo , Consumo de Oxigênio/fisiologiaRESUMO
It is well known that exercise efficiency declines at intensities above the lactate threshold, yet the underlying mechanisms are poorly understood. Some have suggested it is due to a decline in mitochondrial efficiency, but this is difficult to examine in vivo. Therefore, the aim of the current study was to examine how changes in temperature and pH, mimicking those that occur during exercise, affect mitochondrial efficiency in skeletal muscle mitochondria. This study was performed on quadriceps muscle of 20 wild-type mice. Muscle tissue was dissected and either permeabilized (n = 10) or homogenized for isolation of mitochondria (n = 10), and oxidative phosphorylation capacity and P/O ratio were assessed using high-resolution respirometry. Samples from each muscle were analyzed in both normal physiological conditions (37°C, pH 7.4), decreased pH (6.8), increased temperature (40°C), and a combination of both. The combination of increased temperature and decreased pH resulted in a significantly lower P/O ratio, mirrored by an increase in leak respiration and a decrease in respiratory control ratio (RCR), in isolated mitochondria. In permeabilized fibers, RCR and leak were relatively unaffected, though a main effect of temperature was observed. Oxidative phosphorylation capacity was unaffected by changes in pH and temperature in both isolated mitochondria and permeabilized fibers. These results indicate that exercise-like changes in temperature and pH lead to impaired mitochondrial efficiency. These findings offer some degree of support to the concept of decreased mitochondrial efficiency during exercise, and may have implications for the assessment of mitochondrial function related to exercise.NEW & NOTEWORTHY To the best of our knowledge, this is the first study to examine the effects of combined changes in temperature and pH, mimicking intramuscular alterations during exercise. Our findings suggest that mitochondrial efficiency is impaired during exercise of moderate to high intensity, which could be a possible mechanism contributing to the decline in exercise efficiency at intensities above the lactate threshold.
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Mitocôndrias Musculares , Mitocôndrias , Camundongos , Animais , Temperatura , Mitocôndrias Musculares/metabolismo , Mitocôndrias/metabolismo , Músculo Esquelético/metabolismo , Concentração de Íons de Hidrogênio , Lactatos/metabolismo , Consumo de Oxigênio/fisiologiaRESUMO
Ageing, a sedentary lifestyle, and obesity are associated with increased oxidative stress, while regular exercise is associated with an increased antioxidant capacity in trained skeletal muscles. Whether a higher aerobic fitness is associated with increased expression of antioxidant enzymes and their regulatory factors in skeletal muscle remains unknown. Although oestrogens could promote a higher antioxidant capacity in females, it remains unknown whether a sex dimorphism exists in humans regarding the antioxidant capacity of skeletal muscle. Thus, the aim was to determine the protein expression levels of the antioxidant enzymes SOD1, SOD2, catalase and glutathione reductase (GR) and their regulatory factors Nrf2 and Keap1 in 189 volunteers (120 males and 69 females) to establish whether sex differences exist and how age, VO2max and adiposity influence these. For this purpose, vastus lateralis muscle biopsies were obtained in all participants under resting and unstressed conditions. No significant sex differences in Nrf2, Keap1, SOD1, SOD2, catalase and GR protein expression levels were observed after accounting for VO2max, age and adiposity differences. Multiple regression analysis indicates that the VO2max in mL.kg LLM-1.min-1can be predicted from the levels of SOD2, Total Nrf2 and Keap1 (R = 0.58, P < 0.001), with SOD2 being the main predictor explaining 28 % of variance in VO2max, while Nrf2 and Keap1 explained each around 3 % of the variance. SOD1 protein expression increased with ageing in the whole group after accounting for differences in VO2max and body fat percentage. Overweight and obesity were associated with increased pSer40-Nrf2, pSer40-Nrf2/Total Nrf2 ratio and SOD1 protein expression levels after accounting for differences in age and VO2max. Overall, at the population level, higher aerobic fitness is associated with increased basal expression of muscle antioxidant enzymes, which may explain some of the benefits of regular exercise.
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Adiposidade , Antioxidantes , Humanos , Feminino , Masculino , Catalase/genética , Fator 2 Relacionado a NF-E2/genética , Superóxido Dismutase-1 , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Obesidade/genética , Músculo Esquelético , Glutationa RedutaseRESUMO
Hepatic lipid metabolism is highly dynamic, and disruption of several circadian transcriptional regulators results in hepatic steatosis. This includes genetic disruption of the glucocorticoid receptor (GR) as the liver develops. To address the functional role of GR in the adult liver, we used an acute hepatocyte-specific GR knockout model to study temporal hepatic lipid metabolism governed by GR at several preprandial and postprandial circadian timepoints. Lipidomics analysis revealed significant temporal lipid metabolism, where GR disruption results in impaired regulation of specific triglycerides, nonesterified fatty acids, and sphingolipids. This correlates with increased number and size of lipid droplets and mildly reduced mitochondrial respiration, most noticeably in the postprandial phase. Proteomics and transcriptomics analyses suggest that dysregulated lipid metabolism originates from pronounced induced expression of enzymes involved in fatty acid synthesis, ß-oxidation, and sphingolipid metabolism. Integration of GR cistromic data suggests that induced gene expression is a result of regulatory actions secondary to direct GR effects on gene transcription.
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Metabolismo dos Lipídeos , Receptores de Glucocorticoides , Masculino , Animais , Camundongos , Metabolismo dos Lipídeos/genética , Receptores de Glucocorticoides/genética , Hepatócitos , Fígado , AdipogeniaRESUMO
BACKGROUND: Adjuvant chemo- and radiotherapy cause cellular damage to tumorous and healthy dividing cells. Chemotherapy has been shown to cause mitochondrial respiratory dysfunction in non-tumorous tissues, but the effects on human peripheral blood mononuclear cells (PBMCs) remain unknown. AIM: We aimed to investigate mitochondrial respiration of PBMCs before and after adjuvant chemo- and radiotherapy in postmenopausal patients with early breast cancer (EBC) and relate these to metabolic parameters of the patients. METHODS: Twenty-three postmenopausal women diagnosed with EBC were examined before and shortly after chemotherapy with (n = 18) or without (n = 5) radiotherapy. Respiration (O2 flux per million PBMCs) was assessed by high-resolution respirometry of intact and permeabilized PBMCs. Clinical metabolic characteristics and mitochondrial DNA (mtDNA) content of PBMCs (mtDN relative to nuclear DNA) were furthermore assessed. RESULTS: Respiration of intact and permeabilized PBMCs from EBC patients significantly increased with adjuvant chemo- and radiotherapy (p = 6 × 10-5 and p = 1 × 10-7 , respectively). The oxygen flux attributed to specific mitochondrial complexes and respiratory states increased by 17-43% compared to before therapy initiation. Similarly, PBMC mtDNA content increased by 40% (p = 0.002). Leukocytes (p = 0.0001), hemoglobin (p = 0.0003), and HDL cholesterol (p = 0.003) concentrations decreased whereas triglyceride (p = 0.01) and LDL (p = 0.02) concentrations increased after treatment suggesting a worsened metabolic state. None of the metabolic parameters or the mtDNA content of PBMCs correlated significantly with PBMC respiration. CONCLUSION: This study shows that mitochondrial respiration and mtDNA content in circulating PBMCs increase after adjuvant chemo- and radiotherapy in postmenopausal patients with EBC. Besides the increased mtDNA content, a shift in PBMC subpopulation proportions towards cells relying on oxidative phosphorylation, who may be less sensitive to chemotherapy, might influence the increased mitochondrial respiration observed iafter chemotherapy.
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Neoplasias da Mama , Leucócitos Mononucleares , Humanos , Feminino , Leucócitos Mononucleares/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/radioterapia , Mitocôndrias/metabolismo , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , RespiraçãoRESUMO
It has recently been established that myosin, the molecular motor protein, is able to exist in two conformations in relaxed skeletal muscle. These conformations are known as the super-relaxed (SRX) and disordered-relaxed (DRX) states and are finely balanced to optimize ATP consumption and skeletal muscle metabolism. Indeed, SRX myosins are thought to have a 5- to 10-fold reduction in ATP turnover compared with DRX myosins. Here, we investigated whether chronic physical activity in humans would be associated with changes in the proportions of SRX and DRX skeletal myosins. For that, we isolated muscle fibers from young men of various physical activity levels (sedentary, moderately physically active, endurance-trained, and strength-trained athletes) and ran a loaded Mant-ATP chase protocol. We observed that in moderately physically active individuals, the amount of myosin molecules in the SRX state in type II muscle fibers was significantly greater than in age-matched sedentary individuals. In parallel, we did not find any difference in the proportions of SRX and DRX myosins in myofibers between highly endurance- and strength-trained athletes. We did however observe changes in their ATP turnover time. Altogether, these results indicate that physical activity level and training type can influence the resting skeletal muscle myosin dynamics. Our findings also emphasize that environmental stimuli such as exercise have the potential to rewire the molecular metabolism of human skeletal muscle through myosin.
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Miosinas , Miosinas de Músculo Esquelético , Masculino , Humanos , Miosinas de Músculo Esquelético/metabolismo , Miosinas/metabolismo , Músculo Esquelético/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Trifosfato de Adenosina/metabolismoRESUMO
OBJECTIVES: Traditional jumping-dance rituals performed by Maasai men involve prolonged physical exertion that may contribute significantly to overall physical activity level. We aimed to objectively quantify the metabolic intensity of jumping-dance activity and assess associations with habitual physical activity and cardiorespiratory fitness (CRF). METHODS: Twenty Maasai men (18-37 years) from rural Tanzania volunteered to participate in the study. Habitual physical activity was monitored using combined heart rate (HR) and movement sensing over 3 days, and jumping-dance engagement was self-reported. A 1-h jumping-dance session resembling a traditional ritual was organized, during which participants' vertical acceleration and HR were monitored. An incremental, submaximal 8-min step test was performed to calibrate HR to physical activity energy expenditure (PAEE) and assess CRF. RESULTS: Mean (range) habitual PAEE was 60 (37-116) kJ day-1 kg-1 , and CRF was 43 (32-54) mL O2 min-1 kg-1 . The jumping-dance activity was performed at an absolute HR of 122 (83-169) beats·min-1 , and PAEE of 283 (84-484) J min-1 kg-1 or 42 (18-75)% when expressed relative to CRF. The total PAEE for the session was 17 (range 5-29) kJ kg-1 , ~28% of the daily total. Self-reported engagement in habitual jumping-dance frequency was 3.8 (1-7) sessions/week, with a total duration of 2.1 (0.5-6.0) h/session. CONCLUSIONS: Intensity during traditional jumping-dance activity was moderate, but on average sevenfold higher than habitual physical activity. These rituals are common, and can make a substantial contribution to overall physical activity in Maasai men, and thus be promoted as a culture-specific activity to increase energy expenditure and maintain good health in this population.
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Aptidão Cardiorrespiratória , Comportamento Ritualístico , Humanos , Masculino , Exercício Físico/fisiologia , Metabolismo Energético/fisiologia , Teste de Esforço , Aptidão Cardiorrespiratória/fisiologia , Frequência Cardíaca/fisiologiaRESUMO
BACKGROUND: Statin therapy has shown pleiotropic effects affecting both mitochondrial function and inflammatory status. However, few studies have investigated the concurrent effects of statin exposure on mitochondrial function and inflammatory status in human subcutaneous white adipose tissue. OBJECTIVES: In a cross-sectional study, we investigated the effects of simvastatin on mitochondrial function and inflammatory status in subcutaneous white adipose tissue of 55 human participants: 38 patients (19 females/19 males) in primary prevention with simvastatin (> 40 mg/d, > 3 mo) and 17 controls (9 females/8 males) with elevated plasma cholesterol. The 2 groups were matched on age, body mass index, and maximal oxygen consumption. METHODS: Anthropometrics and fasting biochemical characteristics were measured. Mitochondrial respiratory capacity was assessed in white adipose tissue by high-resolution respirometry. Subcutaneous white adipose tissue expression of the inflammatory markers IL-6, chemokine (C-C motif) ligand 2 (CCL2), CCL-5, tumor necrosis factor-α, IL-10, and IL-4 was analyzed by quantitative PCR. RESULTS: Simvastatin-treated patients showed lower plasma cholesterol (P < .0001), low-density lipoprotein (P < .0001), and triglyceride levels (P = .0116) than controls. Simvastatin-treated patients had a lower oxidative phosphorylation capacity of mitochondrial complex II (P = .0001 when normalized to wet weight, P < .0001 when normalized to citrate synthase activity [intrinsic]), and a lower intrinsic mitochondrial electron transport system capacity (P = .0004). Simvastatin-treated patients showed higher IL-6 expression than controls (P = .0202). CONCLUSION: Simvastatin treatment was linked to mitochondrial respiratory capacity in human subcutaneous white adipose tissue, but no clear link was found between statin exposure, respiratory changes, and inflammatory status of adipose tissue.
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Inibidores de Hidroximetilglutaril-CoA Redutases , Sinvastatina , Masculino , Feminino , Humanos , Sinvastatina/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Interleucina-6/metabolismo , Estudos Transversais , Mitocôndrias/metabolismo , Tecido Adiposo Branco/metabolismo , Colesterol/metabolismo , Tecido Adiposo/metabolismoRESUMO
BACKGROUND: Metabolic dysfunction and cachexia are associated with poor cancer prognosis. With no pharmacological treatments, it is crucial to define the molecular mechanisms causing cancer-induced metabolic dysfunction and cachexia. Adenosine monophosphate-activated protein kinase (AMPK) connects metabolic and muscle mass regulation. As AMPK could be a potential treatment target, it is important to determine the function for AMPK in cancer-associated metabolic dysfunction and cachexia. We therefore established AMPK's roles in cancer-associated metabolic dysfunction, insulin resistance and cachexia. METHODS: In vastus lateralis muscle biopsies from n = 26 patients with non-small cell lung cancer (NSCLC), AMPK signalling and protein content were examined by immunoblotting. To determine the role of muscle AMPK, male mice overexpressing a dominant-negative AMPKα2 (kinase-dead [KiDe]) specifically in striated muscle were inoculated with Lewis lung carcinoma (LLC) cells (wild type [WT]: n = 27, WT + LLC: n = 34, mAMPK-KiDe: n = 23, mAMPK-KiDe + LLC: n = 38). Moreover, male LLC-tumour-bearing mice were treated with (n = 10)/without (n = 9) 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) to activate AMPK for 13 days. Littermate mice were used as controls. Metabolic phenotyping of mice was performed via indirect calorimetry, body composition analyses, glucose and insulin tolerance tests, tissue-specific 2-[3H]deoxy-d-glucose (2-DG) uptake and immunoblotting. RESULTS: Patients with NSCLC presented increased muscle protein content of AMPK subunits α1, α2, ß2, γ1 and γ3 ranging from +27% to +79% compared with control subjects. In patients with NSCLC, AMPK subunit protein content correlated with weight loss (α1, α2, ß2 and γ1), fat-free mass (α1, ß2 and γ1) and fat mass (α1 and γ1). Tumour-bearing mAMPK-KiDe mice presented increased fat loss and glucose and insulin intolerance. LLC in mAMPK-KiDe mice displayed lower insulin-stimulated 2-DG uptake in skeletal muscle (quadriceps: -35%, soleus: -49%, extensor digitorum longus: -48%) and the heart (-29%) than that in non-tumour-bearing mice. In skeletal muscle, mAMPK-KiDe abrogated the tumour-induced increase in insulin-stimulated TBC1D4thr642 phosphorylation. The protein content of TBC1D4 (+26%), pyruvate dehydrogenase (PDH; +94%), PDH kinases (+45% to +100%) and glycogen synthase (+48%) was increased in skeletal muscle of tumour-bearing mice in an AMPK-dependent manner. Lastly, chronic AICAR treatment elevated hexokinase II protein content and normalized phosphorylation of p70S6Kthr389 (mTORC1 substrate) and ACCser212 (AMPK substrate) and rescued cancer-induced insulin intolerance. CONCLUSIONS: Protein contents of AMPK subunits were upregulated in skeletal muscle of patients with NSCLC. AMPK activation seemed protectively inferred by AMPK-deficient mice developing metabolic dysfunction in response to cancer, including AMPK-dependent regulation of multiple proteins crucial for glucose metabolism. These observations highlight the potential for targeting AMPK to counter cancer-associated metabolic dysfunction and possibly cachexia.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Camundongos , Masculino , Animais , Monofosfato de Adenosina/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Carcinoma Pulmonar de Células não Pequenas/complicações , Caquexia/etiologia , Caquexia/metabolismo , Neoplasias Pulmonares/complicações , Glucose/metabolismo , Músculo Esquelético/metabolismo , Insulina/metabolismoRESUMO
This review provides an overview of the evidence regarding mtDNA and valid biomarkers for assessing mitochondrial adaptions. Mitochondria are small organelles that exist in almost all cells throughout the human body. As the only organelle, mitochondria contain their own DNA, mitochondrial DNA (mtDNA). mtDNA-encoded polypeptides are subunits of the enzyme complexes in the electron transport chain (ETC) that are responsible for production of ATP to the cells. mtDNA is frequently used as a biomarker for mitochondrial content, since changes in mitochondrial volume are thought to induce similar changes in mtDNA. However, some exercise studies have challenged this "gene-dosage theory", and have indicated that changes in mitochondrial content can adapt without changes in mtDNA. Thus, the aim of this scoping review was to summarize the studies that used mtDNA as a biomarker for mitochondrial adaptions and address the question as to whether changes in mitochondrial content, induce changes in mtDNA in response to aerobic exercise in the healthy skeletal muscle. The literature was searched in PubMed and Embase. Eligibility criteria included: interventional study design, aerobic exercise, mtDNA measurements reported pre- and postintervention for the healthy skeletal muscle and English language. Overall, 1585 studies were identified. Nine studies were included for analysis. Eight out of the nine studies showed proof of increased oxidative capacity, six found improvements in mitochondrial volume, content and/or improved mitochondrial enzyme activity and seven studies did not find evidence of change in mtDNA copy number. In conclusion, the findings imply that mitochondrial adaptions, as a response to aerobic exercise, can occur without a change in mtDNA copy number.
Assuntos
DNA Mitocondrial , Mitocôndrias , Humanos , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Mitocôndrias/genética , Músculo Esquelético/metabolismo , Exercício Físico , Biomarcadores/metabolismo , Mitocôndrias Musculares/genética , Mitocôndrias Musculares/metabolismoRESUMO
Alternate-day fasting induces oscillations in energy stores. We hypothesized that repeated oscillations increases insulin secretion and sensitivity, and improve metabolic health in patients with obesity with or without type 2 diabetes (T2DM). Twenty-three male patients fasted every other day for 30 h for 6 weeks. Experiments included resting energy expenditure, continuous glucose monitoring, intravenous glucose tolerance test, euglycemic hyperinsulinemic clamp, body composition, hepatic triglyceride content, muscle biopsies which were performed at baseline, during 3 weeks without allowed weight loss, and after additional 3 weeks with weight loss. Bodyweight decreased â¼1% and further â¼3% during weeks one to three and four to six, respectively (p < 0.05). Only minor changes in fat mass occurred in weeks 1-3. With weight loss, visceral fat content decreased by 13 ± 3% and 12 ± 2% from baseline in patients with and without T2DM, respectively (p < 0.05). Hepatic triglyceride content decreased by 17 ± 9% and 36 ± 9% (with diabetes) and 27 ± 8% and 40 ± 8% (without diabetes) from baseline to week 3 and week 6, respectively (all p < 0.05). Muscle lipid and glycogen content oscillated with the intervention. Glucose homeostasis, insulin secretion and sensitivity was impaired in patients with T2DM and did not change without weight loss, but improved (p < 0.05) when alternate day fasting was combined with weight loss. In conclusion, alternate-day fasting is feasible in patients with obesity and T2DM, and decreases visceral fat and liver fat deposits. Energy store oscillations by alternate-day fasting do not improve insulin secretion or sensitivity per se. Clinical Trial registration: (ClinicalTrials.gov), (ID NCT02420054).