It has been proposed that skeletal muscle insulin resistance arises from the accumulation of intramyocellular lipid metabolites that impede insulin signaling, including diacylglycerol and ceramide. ...We determined the role of de novo ceramide synthesis in mediating muscle insulin resistance.
Mice were subjected to 12 weeks of diet-induced obesity (DIO), and then treated for 4 weeks with myriocin, an inhibitor of serine palmitoyl transferase-1 (SPT1), the rate-limiting enzyme of de novo ceramide synthesis.
After 12 weeks of DIO, C57BL/6 mice demonstrated a doubling in gastrocnemius ceramide content, which was completely reversed (141.5 ± 15.8 vs. 94.6 ± 10.2 nmol/g dry wt) via treatment with myriocin, whereas hepatic ceramide content was unaffected by DIO. Interestingly, myriocin treatment did not alter the DIO-associated increase in gastrocnemius diacyglycerol content, and the only correlation observed between lipid metabolite accumulation and glucose intolerance occurred with ceramide (R = 0.61). DIO mice treated with myriocin showed a complete reversal of glucose intolerance and insulin resistance which was associated with enhanced insulin-stimulated Akt and glycogen synthase kinase 3β phosphorylation. Furthermore, myriocin treatment also decreased intramyocellular ceramide content and prevented insulin resistance development in db/db mice. Finally, myriocin-treated DIO mice displayed enhanced oxygen consumption rates (3,041 ± 124 vs. 2,407 ± 124 ml/kg/h) versus their control counterparts.
Our results demonstrate that the intramyocellular accumulation of ceramide correlates strongly with the development of insulin resistance, and suggests that inhibition of SPT1 is a potentially promising target for the treatment of insulin resistance.
Introduction
High-intensity interval training (HIIT) and sprint interval training (SIT) consistently elevate post-exercise metabolism compared to moderate-intensity continuous training (MICT) in ...young adults (18–25 years), however few studies have investigated this in middle-aged adults.
Purpose
To assess the effect of exercise intensity on post-exercise metabolism following submaximal, near-maximal, and supramaximal exercise protocols in middle-aged adults.
Methods
12 participants (8 females; age: 44 ± 10 years;
V
˙
O
2max
: 35.73 ± 9.97 mL·kg
−1
min
−1
) had their oxygen consumption (
V
˙
O
2
) measured during and for 2 h following 4 experimental sessions: (1) no-exercise control (CTRL); (2) MICT exercise (30 min at 65%
V
˙
O
2max
); (3) HIIT exercise (10 × 1 min at 90% maximum heart rate with 1 min rest); and (4) modified-SIT exercise (8 × 15 s “all-out” efforts with 2 min rest). Between session differences for
V
˙
O
2
and fat oxidation were compared.
Results
O
2
consumed post-exercise was elevated during the 1st h and 2nd h following HIIT (15.9 ± 2.6, 14.7 ± 2.3 L; P < 0.036,
d
> 0.98) and modified-SIT exercise (16.9 ± 3.3, 15.30 ± 3.4 L; P < 0.041,
d
> 0.96) compared to CTRL (13.3 ± 1.9, 12.0 ± 2.5 L) while modified-SIT was also elevated vs HIIT in the 1st h (P < 0.041,
d
> 0.96). Total post-exercise O
2
consumption was elevated following all exercise sessions (MICT: 27.7 ± 4.1, HIIT: 30.6 ± 4.8, SIT: 32.2 ± 6.6 L; P < 0.027,
d
> 1.03) compared to CTRL (24.9 ± 4.1 L). Modified-SIT exercise increased fat oxidation (0.103 ± 0.019 g min
−1
) compared to all sessions post-exercise (CTRL: 0.059 ± 0.025, MICT: 0.075 ± 0.022, HIIT: 0.081 ± 0.021 g·min
−1
; P < 0.007,
d
> 1.30) and HIIT exercise increased compared to CTRL (P = 0.046,
d
= 0.87).
Conclusion
Exercise intensity has an important effect on post-exercise metabolism in middle-aged adults.
Oxygen is required for the survival of the majority of eukaryotic organisms, as it is important for many cellular processes. Eukaryotic cells utilize oxygen for the production of biochemical energy ...in the form of adenosine triphosphate (ATP) generated from the catabolism of carbon-rich fuels such as glucose, lipids and glutamine. The intracellular sites of oxygen consumption-coupled ATP production are the mitochondria, double-membraned organelles that provide a dynamic and multifaceted role in cell signalling and metabolism. Highly evolutionarily conserved molecular mechanisms exist to sense and respond to changes in cellular oxygen levels. The primary transcriptional regulators of the response to decreased oxygen levels (hypoxia) are the hypoxia-inducible factors (HIFs), which play important roles in both physiological and pathophysiological contexts. In this review we explore the relationship between HIF-regulated signalling pathways and the mitochondria, including the regulation of mitochondrial metabolism, biogenesis and distribution.
Exercise adherence is affected by factors including perceptions of enjoyment, time availability, and intrinsic motivation. Approximately 50% of individuals withdraw from an exercise program within ...the first 6 mo of initiation, citing lack of time as a main influence. Time efficient exercise such as high intensity interval training (HIIT) may provide an alternative to moderate intensity continuous exercise (MICT) to elicit substantial health benefits. This study examined differences in enjoyment, affect, and perceived exertion between MICT and HIIT. Twelve recreationally active men and women (age = 29.5 ± 10.7 yr, VO2max = 41.4 ± 4.1 mL/kg/min, BMI = 23.1 ± 2.1 kg/m2) initially performed a VO2max test on a cycle ergometer to determine appropriate workloads for subsequent exercise bouts. Each subject returned for two additional exercise trials, performing either HIIT (eight 1 min bouts of cycling at 85% maximal workload (Wmax) with 1 min of active recovery between bouts) or MICT (20 min of cycling at 45% Wmax) in randomized order. During exercise, rating of perceived exertion (RPE), affect, and blood lactate concentration (BLa) were measured. Additionally, the Physical Activity Enjoyment Scale (PACES) was completed after exercise. Results showed higher enjoyment (p = 0.013) in response to HIIT (103.8 ± 9.4) versus MICT (84.2 ± 19.1). Eleven of 12 participants (92%) preferred HIIT to MICT. However, affect was lower (p<0.05) and HR, RPE, and BLa were higher (p<0.05) in HIIT versus MICT. Although HIIT is more physically demanding than MICT, individuals report greater enjoyment due to its time efficiency and constantly changing stimulus.
NCT:02981667.
Military and/or emergency services personnel may be required to perform high-intensity physical activity during exposure to elevated inspired carbon dioxide (CO
). Although many of the physiological ...consequences of hypercapnia are well characterized, the effects of graded increases in inspired CO
on self-paced endurance performance have not been determined. The aim of this study was to compare the effects of 0%, 2%, and 4% inspired CO
on 2-mile run performance, as well as physiological and perceptual responses during time trial exercise. Twelve physically active volunteers (peak oxygen uptake = 49 ± 5 mL·kg
·min
; 3 women) performed three experimental trials in a randomized, single-blind, crossover manner, breathing 21% oxygen with either 0%, 2%, or 4% CO
. During each trial, participants completed 10 min of walking at ∼40% peak oxygen uptake followed by a self-paced 2-mile treadmill time trial. One participant was unable to complete the 4% CO
trial due to lightheadedness during the run. Compared with the 0% CO
trial, run performance was 5 ± 3% and 7 ± 3% slower in the 2% and 4% CO
trials, respectively (both
< 0.001). Run performance was significantly slower with 4% versus 2% CO
(
= 0.046). The dose-dependent performance impairments were accompanied by stepwise increases in mean ventilation, despite significant reductions in running speed. Dyspnea and headache were significantly elevated during the 4% CO
trial compared with both the 0% and 2% trials. Overall, our findings show that graded increases in inspired CO
impair endurance performance in a stepwise manner in healthy humans.
We investigated the effects of individualised combined resistance and aerobic exercise on microvascular and macrovascular function in rheumatoid arthritis (RA) patients.
Forty age-matched, ...gender-matched and body mass index (BMI)-matched patients were allocated to either an exercise group, receiving a 6 months tailored aerobic and resistance exercise intervention, or controls receiving only information about the benefits of exercise. Participants were assessed for microvascular (acetylcholine (Ach) and sodium nitroprusside (SNP)) and macrovascular (flow-mediated dilatation (FMD) and glyceryl trinitrate (GTN)) endothelial function, maximal oxygen uptake, disease activity and severity (C-reactive protein (CRP), disease activity score 28 and health assessment questionnaire). Data were collected at baseline, 3 months and at the end of the intervention (6 months).
At baseline, demographic, anthropometric, disease-related characteristics and endothelial function parameters were similar between the exercise and control groups (p>0.05). Repeated measures analysis of variance revealed a significant improvement in endothelial function parameters at 3 (GTN: p<0.001) or 6 months (Ach: p=0.016, SNP: p=0.045, FMD: p=0.016) in the exercise but not in the control group. Generalised estimated equations detected that maximal oxygen uptake was a strong predictor for the observed changes in Ach (p=0.009) and GTN (p<0.001) whereas logCRP for SNP (p=0.017) and GTN (p=0.008).
An exercise programme designed to meet individual needs and physical abilities significantly improves microvascular and macrovascular function in parallel with disease-related characteristics in RA patients. The potential long-term beneficial effects of such interventions at reducing cardiovascular risk in these patients merit further exploration.
ISRCTN50861407.
This study compared differences in cardiovascular (CV) risk factor responses between males and females following endurance (END) and resistance (RES) training. We present the frequency of responders ...to each training modality and the magnitude of response. Using a randomized crossover design, 68 healthy adults age: female (F): 24.5 ± 4.6; male (M): 27.3 ± 6.6 completed 3 mo of RES and END, with 3 mo washout. Peak oxygen consumption (V̇o
), strength, body composition, blood pressure, glucose, insulin, and lipids were measured. V̇o
(L/min) significantly increased in both sexes following END, but not RES. The magnitude of change was larger in males (F: +0.20 L/min; M: +0.32 L/min), although this did not achieve statistical significance (
= 0.051). Strength significantly increased in both sexes following RES (
< 0.01), with a larger increase in males (Leg press: F: +39 kg; M: +63 kg;
< 0.05). Lean mass significantly increased in both sexes (
< 0.01) following RES and fat mass decreased in females following END (
= 0.019). The change in C-reactive protein following END was significantly different between sexes (F: -0.4 mg/L; M: +0.5 mg/L;
= 0.035). There were no differences between sexes in the proportion of individuals who responded positively to any variable following RES or END; differences between sexes were due to the magnitude of change. Males had a larger increase in V̇o
following END and strength following RES. There were no sex differences in other CV risk factors. This suggests differences in physiological responses to strength and V̇o
may not translate to changes in CV risk in healthy subjects.
This study investigated sex differences in cardiovascular risk factors in response to different exercise training modalities. Males had a larger improvement in peak oxygen consumption following endurance training and strength following resistance training compared with females. These changes in peak oxygen consumption and strength did not translate to changes in other cardiovascular risk factors. Despite the greater magnitude of change in males, there were no sex differences in the proportion of individuals who responded to training.
Analyzing metabolism of peripheral blood mononuclear cells (PBMCs) can possibly serve as a cellular metabolic read-out for lifestyle factors and lifestyle interventions. However, the impact of PBMC ...composition on PBMC metabolism is not yet clear, neither is the differential impact of a longer-term lifestyle factor versus a short-term lifestyle intervention. We investigated the effect of aerobic fitness level and a recent exercise bout on PBMC metabolism in females. PBMCs from 31 young female adults divided into a high-fit (V̇o
≥ 47 mL/kg/min,
= 15) and low-fit (V̇o
≤ 37 mL/kg/min,
= 16) groups were isolated at baseline and overnight after a single bout of exercise (60 min, 70% V̇o
). Oxygen consumption rate (OCR) and glycolytic rate (GR) were measured using extracellular flux (XF) assays and PBMC subsets were characterized using fluorescence-activated cell sorting (FACS). Basal OCR, FCCP-induced OCR, spare respiratory capacity, ATP-linked OCR, and proton leak were significantly higher in high-fit than in low-fit females (all
< 0.01), whereas no significant differences in glycolytic rate (GR) were found (all
> 0.05). A recent exercise bout did not significantly affect GR or OCR parameters (all
> 0.05). The overall PBMC composition was similar between high-fit and low-fit females. Mitochondrial PBMC function was significantly higher in PBMCs from high-fit than from low-fit females, which was unrelated to PBMC composition and not impacted by a recent bout of exercise. Our study reveals a link between PBMC metabolism and levels of aerobic fitness, increasing the relevance of PBMC metabolism as a marker to study the impact of lifestyle factors on human health.
Mitochondrial metabolism was significantly higher in PBMCs from high-fit than from low-fit females. This was unrelated to PBMC composition and not impacted by a recent bout of exercise. Our study reveals a link between PBMC metabolism and levels of aerobic fitness, increasing the relevance of PBMC metabolism as a marker to study the impact of lifestyle factors on human health.
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