Impaired cardiac reserve and severely diminished skeletal muscle O2 utilization mediate exercise intolerance in Barth syndrome

2011 ◽  
Vol 301 (5) ◽  
pp. H2122-H2129 ◽  
Author(s):  
Carolyn T. Spencer ◽  
Barry J. Byrne ◽  
Randall M. Bryant ◽  
Renee Margossian ◽  
Melissa Maisenbacher ◽  
...  

Barth syndrome (BTHS) is a mitochondrial myopathy characterized by reports of exercise intolerance. We sought to determine if 1) BTHS leads to abnormalities of skeletal muscle O2 extraction/utilization and 2) exercise intolerance in BTHS is related to impaired O2 extraction/utilization, impaired cardiac function, or both. Participants with BTHS (age: 17 ± 5 yr, n = 15) and control participants (age: 13 ± 4 yr, n = 9) underwent graded exercise testing on a cycle ergometer with continuous ECG and metabolic measurements. Echocardiography was performed at rest and at peak exercise. Near-infrared spectroscopy of the vastus lateralis muscle was continuously recorded for measurements of skeletal muscle O2 extraction. Adjusting for age, peak O2 consumption (16.5 ± 4.0 vs. 39.5 ± 12.3 ml·kg−1·min−1, P < 0.001) and peak work rate (58 ± 19 vs. 166 ± 60 W, P < 0.001) were significantly lower in BTHS than control participants. The percent increase from rest to peak exercise in ejection fraction (BTHS: 3 ± 10 vs. control: 19 ± 4%, P < 0.01) was blunted in BTHS compared with control participants. The muscle tissue O2 saturation change from rest to peak exercise was paradoxically opposite (BTHS: 8 ± 16 vs. control: −5 ± 9, P < 0.01), and the deoxyhemoglobin change was blunted (BTHS: 0 ± 12 vs. control: 10 ± 8, P < 0.09) in BTHS compared with control participants, indicating impaired skeletal muscle extraction in BTHS. In conclusion, severe exercise intolerance in BTHS is due to both cardiac and skeletal muscle impairments that are consistent with cardiac and skeletal mitochondrial myopathy. These findings provide further insight to the pathophysiology of BTHS.

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Carolyn T Spencer ◽  
Randall M Bryant ◽  
Barry Byrne ◽  
Elisabeth Heal ◽  
Renee Margossian ◽  
...  

Objective s: Barth Syndrome (BTHS) is an X-linked mutation in the TAZ gene characterized by cardiolipin deficiency, mitochondrial dysfunction and cardio-skeletal myopathy. We hypothe- sized that abnormal skeletal muscle oxygen (O 2 ) utilization contributes to exercise intolerance in BTHS. Methods : Boys with BTHS (n=13) and healthy male controls (n=7) performed a graded exercise test on a cycle ergometer with continuous metabolic and EKG monitoring. Near infrared spectroscopy (NIRS), an indirect measure of tissue O 2 saturation and index of skeletal muscle O 2 utilization, was applied to the vastus lateralis during exercise. Cardiac function in BTHS was assessed by echocardiography and serum BNP to examine the relationship between resting cardiac function and exercise capacity in BTHS. Results : Age (16±5 vs 13±3 years; p=0.22), BMI (17±3 vs. 20±5; p=0.14) and BSA (1.0±0.5 vs 1.2±0.6 m 2 ; p=0.3) were not different between BTHS and controls. BTHS had lower peak VO 2 (19±6 vs. 52±6 ml/kg/min, p < 0.001), lower % of predicted peak VO 2 (40±10% vs. 115±12%, p=0.0004), lower peak work rate (58±18 vs. 205±69 watts, p=0.0004), and lower peak O 2 pulse (4.6±1.6 vs. 14±6 ml O 2 /kg/beat, p< 0.00001) than controls. Peak HR in BTHS was lower but remained within normal peak predicted rate (172±14 vs. 197±11 bpm, p=0.001). Vastus lateralis tissue O 2 saturation at peak exercise decreased from baseline in controls as expected (-18±16%, p<0.001) but paradoxically increased from baseline in BTHS (+17±14%, p<0.03, p=0.0005 BTHS vs. controls) indicating impaired muscle O 2 utilization. Absolute (r= - 0.70, p<0.0001) and percent (r= - 0.70, p<0.001) change in NIRS from baseline was negatively associated with peak VO 2 . There was no correlation between peak VO 2 and resting EF (55±7%; r=0.12), SF (30±4%; r= -.26), myocardial performance index (0.4±0.1; r= -.3) or serum BNP (232±381; r=0.1). Conclusion : O 2 consumption during exercise in BTHS is severely reduced and caused, at least in part, by impaired skeletal muscle O 2 utilization. Resting cardiac function is not related to O 2 consumption in BTHS but cardiac dysfunction during exercise in BTHS is not excluded without further studies. Mitochondrial dysfunction likely mediates skeletal muscle O 2 utilization deficits during exercise in BTHS.


1995 ◽  
Vol 269 (6) ◽  
pp. H1949-H1954 ◽  
Author(s):  
R. M. McAllister ◽  
M. D. Delp ◽  
K. A. Thayer ◽  
M. H. Laughlin

Hypothyroidism is characterized by exercise intolerance. We hypothesized that active muscle blood flow during in vivo exercise is inadequate in the hypothyroid state. Additionally, we hypothesized that endurance exercise training would restore normal blood flow during acute exercise. To test these hypotheses, rats were made hypothyroid (Hypo) over 3-4 mo with propylthiouracil. A subset of Hypo rats was trained (THypo) on a treadmill at 30 m/min (15% grade) for 60 min/day 5 days/wk over 10-15 wk. Hypothyroidism was evidenced by approximately 80% reductions in plasma triiodothyronine levels in Hypo and THypo and by 40-50% reductions in citrate synthase activities in high oxidative muscles in Hypo compared with euthyroid (Eut) rats. Training efficacy was indicated by increased (25-100%) citrate synthase activities in muscles of THypo vs. Hypo. Regional blood flows were determined by the radiolabeled microsphere method before exercise and at 1-2 min of treadmill running at 15 m/min (0% grade). Preexercise muscle blood flows were generally similar among groups. During exercise, however, flows were lower in Hypo than in Eut for high oxidative muscles such as the red section of vastus lateralis [277 +/- 24 and 153 +/- 13 (SE) ml.min-1.100 g-1 for Eut and Hypo, respectively; P < 0.01] and vastus intermedius (317 +/- 32 and 187 +/- 20 ml.min-1.100 g-1 for Eut and Hypo, respectively; P < 0.01) muscles. Training (THypo) did not normalize these flows (168 +/- 24 and 181 +/- 24 ml.min-1.100 g-1 for red section of vastus lateralis and vastus intermedius muscles, respectively). Blood flows to low oxidative muscle, such as the white section of vastus lateralis muscle, were similar among groups (21 +/- 5, 25 +/- 4, and 34 +/- 7 ml.min-1.100 g-1 for Eut, Hypo, and THypo, respectively; P = NS). These findings indicate that hypothyroidism is associated with reduced blood flow to skeletal muscle during exercise, suggesting that impaired delivery of nutrients to and/or removal of metabolites from skeletal muscle contributes to the poor exercise tolerance characteristic of hypothyroidism.


Author(s):  
Lucas de Marchi Silva ◽  
Mara Patricia Tarina Chacon Mikahil ◽  
Alex Castro ◽  
Renata Garbellini Duft ◽  
Marina Lívia Venturini Ferreira ◽  
...  

High cardiorespiratory fitness levels (CRF) are strongly associated with reduction of risk of all-cause and cardiovascular disease mortality. CRF can be assessed by maximal oxygen uptake (VO2MAX) or maximal power output (MPO). Skeletal muscle is the main organ responsible for peripheral adaptations related to CRF improvement. In this sense, metabolomics has been pointing out as a potential tool to identify muscular metabolic signature in response to exercise and different phenotypes. Therefore, this study aimed to investigate metabolites in human skeletal muscle associated with CRF. Participated in this study 70 sedentary young men (18-30 years old). Vastus lateralis muscle biopsies were collected at fasting state (12 h). After 72 h, CRF was assessed by MPO, obtained during a maximal incremental test performed until voluntary exhaustion in cycle ergometer, followed by re-test 48 h later. Skeletal muscle samples were analysed through metabolomics (H1 NMR spectroscopy). Associations of baseline metabolites with MPO were explored via three analytical strategies: (1) correlations with gains in MPO; (2) significant difference between groups of and Low CRF and High CRF; and (3) metabolite contribution to significant pathways related to MPO. The significance level was P < 0.01 or false discovery rate of 0.1. From 70 identified metabolites, only Formate and NADP+ were supported by the three levels of evidence. Intrinsic CRF levels are associated with higher baseline metabolities.


Author(s):  
Margaret N. Deane ◽  
Michael Gregory ◽  
Maurice Mars

The effect that compressed air massage (CAM) has on skeletal muscle has been ascertained by the morphological and morphometric evaluation of healthy vervet monkey and rabbit skeletal muscle. How CAM may influence the process of healing following a contusion injury is not known. To determine how CAM or other physiotherapeutic modalities may influence healing, it is necessary to create a minor injury that is both reproducible and quantifiable at the termination of a pre-determined healing period. An earlier study described changes in the morphology of skeletal muscle following a reproducible contusion injury. This study extended that work in that it attempted to quantify the ‘severity’ of such an injury. A 201 g, elongated oval-shaped weight was dropped seven times through a 1 m tube onto the left vastus lateralis muscle of four New Zealand white rabbits. Biopsies were obtained 6 days after injury from the left healing juxta-bone and sub-dermal muscle and uninjured (control) right vastus lateralis of each animal. The tissue was fixed in formal saline, embedded in wax, cut and stained with haematoxylin and phosphotungstic haematoxylin. The muscle was examined by light microscopy and quantification of the severity of injury made using a modified, ‘in-house’ morphological index and by the comparative morphometric measurement of the cross-sectioned epimysium and myofibres in injured and control muscle. The results showed that a single contusion causes multiple, quantifiable degrees of injury from skin to bone – observations of particular importance to others wishing to investigate contusion injury in human or animal models.


1992 ◽  
Vol 73 (5) ◽  
pp. 1873-1880 ◽  
Author(s):  
A. R. Coggan ◽  
W. M. Kohrt ◽  
R. J. Spina ◽  
J. P. Kirwan ◽  
D. M. Bier ◽  
...  

The purpose of this study was to test the hypothesis that the rate of plasma glucose oxidation during exercise is inversely related to muscle respiratory capacity. To this end, 14 subjects were studied: in 7 of these subjects, the blood lactate threshold (LT) occurred at a relatively high intensity [i.e., at 65 +/- 2% of peak cycle ergometer oxygen uptake (VO2 peak)], whereas in the other 7 subjects, LT occurred at a relatively low intensity (i.e., at 45 +/- 2% of VO2 peak). VO2peak did not differ between the two groups, but citrate synthase activity in the vastus lateralis muscle was 53% higher (P < 0.05) in the high LT group. A primed continuous infusion of [U-13C]glucose was used to quantify rates of glucose appearance (Ra), disappearance (Rd), and oxidation (R(ox)) during 90 min of exercise at 55% VO2peak. Although both absolute and relative rates of oxygen uptake during exercise were similar in the two groups, mean Ra and Rd were 17% lower (P < 0.001) in the high LT group, and mean R(ox) was 25% lower (21.0 +/- 2.6 vs. 27.9 +/- 2.6 mumol.min-1.kg-1; P < 0.001). The percentage of total energy derived from glucose oxidation was inversely related to muscle citrate synthase activity (r = -0.85; P < 0.01). These data support the concept that skeletal muscle respiratory capacity has a major role in determining the metabolic response to submaximal exercise.


Author(s):  
Norita Gildea ◽  
Adam McDermott ◽  
Joel Rocha ◽  
Donal O'Shea ◽  
Simon Green ◽  
...  

We assessed the time course of changes in oxygen uptake (V̇O2) and muscle deoxygenation (i.e., deoxygenated haemoglobin and myoglobin, [HHb+Mb]) kinetics during transitions to moderate-intensity cycling following 12-weeks of low-volume high-intensity interval training (HIIT) vs. moderate-intensity continuous training (MICT) in adults with type 2 diabetes (T2D). Participants were randomly assigned to MICT (n=10, 50 min of moderate-intensity cycling), HIIT (n=9, 10x1 min at ~90% maximal heart rate) or non-exercising control (n=9) groups. Exercising groups trained 3 times per week and measurements were taken every 3 weeks. [HHb+Mb] kinetics were measured by near-infrared spectroscopy at the vastus lateralis muscle. The local matching of O2 delivery to O2 utilization was assessed by the Δ[HHb+Mb]/ΔV̇O2ratio. The pretraining time constant of the primary phase of V̇O2 (τV̇O2p ) decreased (P<0.05) at wk 3 of training in both MICT (from 44±12 to 32±5 s) and HIIT (from 42±8 to 32 ± 4 s) with no further changes thereafter; while no changes were reported in controls. The pretraining overall dynamic response of muscle deoxygenation (τ'[HHb+Mb]) was faster than τV̇O2p in all groups, resulting in Δ[HHb+Mb]/V̇O2p showing a transient "overshoot" relative to the subsequent steady-state level. After 3 wks, the Δ[HHb+Mb]/V̇O2p overshoot was eliminated only in the training groups, so that τ'[HHb+Mb] was not different to τV̇O2p in MICT and HIIT. The enhanced V̇O2 kinetics response consequent to both MICT and HIIT in T2D was likely attributed to a training-induced improvement in matching of O2 delivery to utilization.


1989 ◽  
Vol 66 (1) ◽  
pp. 72-78 ◽  
Author(s):  
L. Martineau ◽  
I. Jacobs

The effects of intramuscular glycogen availability on human temperature regulation were studied in eight seminude subjects immersed in 18 degrees C water for 90 min or until rectal temperature (Tre) decreased to 35.5 degrees C. Each subject was immersed three times over a 3-wk period. Each immersion followed 2.5 days of a specific dietary and/or exercise regimen designed to elicit low (L), normal (N), or high (H) glycogen levels in large skeletal muscle groups. Muscle glycogen concentration was determined in biopsies taken from the vastus lateralis muscle before and after each immersion. Intramuscular glycogen concentration before the immersion was significantly different among the L, N, and H trials (P less than 0.01), averaging 247 +/- 15, 406 +/- 23, and 548 +/- 42 (SE) mmol glucose units.kg dry muscle-1, respectively. The calculated metabolic heat production during the first 30 min of immersion was significantly lower during L compared with N or H (P less than 0.05). The rate at which Tre decreased was more rapid during the L immersion than either N or H (P less than 0.05), and the time during the immersion at which Tre first began to decrease also appeared sooner during L than N or H. The results suggest that low skeletal muscle glycogen levels are associated with more rapid body cooling during water immersion in humans. Higher than normal muscle glycogen levels, however, do not increase cold tolerance.


2007 ◽  
Vol 102 (6) ◽  
pp. 2346-2351 ◽  
Author(s):  
E. Rullman ◽  
H. Rundqvist ◽  
D. Wågsäter ◽  
H. Fischer ◽  
P. Eriksson ◽  
...  

The aims of this study were 1) to characterize changes in matrix metalloproteinase (MMP), endostatin, and vascular endothelial growth factor (VEGF)-A expression in skeletal muscle in response to a single bout of exercise in humans; and 2) to determine if any exchange of endostatin and VEGF-A between circulation and the exercising leg is associated with a change in the tissue expression or plasma concentration of these factors. Ten healthy males performed 65 min of cycle exercise, and muscle biopsies were obtained from the vastus lateralis muscle at rest and immediately and 120 min after exercise. In the muscle biopsies, measurements of mRNA expression levels of MMP-2, MMP-9, MMP-14, and tissue inhibitor of metalloproteinase; VEGF and endostatin protein levels; and MMP activities were performed. Femoral arterial and venous concentrations of VEGF-A and endostatin were determined before, during, and 120 min after exercise. A single bout of exercise increased MMP-9 mRNA and activated MMP-9 protein in skeletal muscle. No measurable increase of endostatin was observed in the skeletal muscle or in plasma following exercise. A concurrent increase in skeletal muscle VEGF-A mRNA and protein levels was induced by exercise, with no signs of peripheral uptake from the circulation. However, a decrease in plasma VEGF-A concentration occurred following exercise. Thus 1) a single bout of exercise activated the MMP system without any resulting change in tissue endostatin protein levels, and 2) the increased VEGF-A protein levels are due to changes in the skeletal muscle tissue itself. Other mechanisms are responsible for the observed exercise-induced decrease in VEGF-A in plasma.


2018 ◽  
Vol 125 (5) ◽  
pp. 1636-1645 ◽  
Author(s):  
Kevin J. Gries ◽  
Ulrika Raue ◽  
Ryan K. Perkins ◽  
Kaleen M. Lavin ◽  
Brittany S. Overstreet ◽  
...  

The purpose of this study was to examine the effects of aerobic lifelong exercise (LLE) on maximum oxygen consumption (V̇o2max) and skeletal muscle metabolic fitness in trained women ( n = 7, 72 ± 2 yr) and men ( n = 21, 74 ± 1 yr) and compare them to old, healthy nonexercisers (OH; women: n = 10, 75 ± 1 yr; men: n = 10, 75 ± 1 yr) and young exercisers (YE; women: n = 10, 25 ± 1 yr; men: n = 10, 25 ± 1 yr). LLE men were further subdivided based on intensity of lifelong exercise and competitive status into performance (LLE-P, n = 14) and fitness (LLE-F, n = 7). On average, LLE exercised 5 day/wk for 7 h/wk over the past 52 ± 1 yr. Each subject performed a maximal cycle test to assess V̇o2maxand had a vastus lateralis muscle biopsy to examine capillarization and metabolic enzymes [citrate synthase, β-hydroxyacyl-CoA dehydrogenase (β-HAD), and glycogen phosphorylase]. V̇o2maxhad a hierarchical pattern (YE > LLE > OH, P < 0.05) for women (44 ± 2 > 26 ± 2 > 18 ± 1 ml·kg−1·min−1) and men (53 ± 3 > 34 ± 1 > 22 ± 1 ml·kg−1·min−1) and was greater ( P < 0.05) in LLE-P (38 ± 1 ml·kg−1·min−1) than LLE-F (27 ± 2 ml·kg−1·min−1). LLE men regardless of intensity and women had similar capillarization and aerobic enzyme activity (citrate synthase and β-HAD) as YE, which were 20%–90% greater ( P < 0.05) than OH. In summary, these data show a substantial V̇o2maxbenefit with LLE that tracked similarly between the sexes, with further enhancement in performance-trained men. For skeletal muscle, 50+ years of aerobic exercise fully preserved capillarization and aerobic enzymes, regardless of intensity. These data suggest that skeletal muscle metabolic fitness may be easier to maintain with lifelong aerobic exercise than more central aspects of the cardiovascular system.NEW & NOTEWORTHY Lifelong exercise (LLE) is a relatively new and evolving area of study with information especially limited in women and individuals with varying exercise intensity habits. These data show a substantial maximal oxygen consumption benefit with LLE that tracked similarly between the sexes. Our findings contribute to the very limited skeletal muscle biopsy data from LLE women (>70 yr), and similar to men, revealed a preserved metabolic phenotype comparable to young exercisers.


1999 ◽  
Vol 86 (2) ◽  
pp. 687-693 ◽  
Author(s):  
Maureen J. MacDonald ◽  
Mark A. Tarnopolsky ◽  
Howard J. Green ◽  
Richard L. Hughson

We hypothesized that near-infrared spectroscopy (NIRS) measures of hemoglobin and/or myoglobin O2 saturation (IR-So 2) in the vascular bed of exercising muscle would parallel changes in femoral venous O2 saturation (S[Formula: see text]) at the onset of leg-kicking exercise in humans. Six healthy subjects performed transitions from rest to 48 ± 3 (SE)-W two-legged kicking exercise while breathing 14, 21, or 70% inspired O2. IR-So 2 was measured over the vastus lateralis muscle continuously during all tests, and femoral venous and radial artery blood samples were drawn simultaneously during rest and during 5 min of exercise. In all gas-breathing conditions, there was a rapid decrease in both IR-So 2 and SfvO2 at the onset of moderate-intensity leg-kicking exercise. Although SfvO2 remained at low levels throughout exercise, IR-So 2increased significantly after the first minute of exercise in both normoxia and hyperoxia. Contrary to the hypothesis, these data show that NIRS does not provide a reliable estimate of hemoglobin and/or O2 saturation as reflected by direct femoral vein sampling.


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