Publications by authors named "Jeroen A L Jeneson"

28 Publications

  • Page 1 of 1

Motor Unit and Capillary Recruitment During Fatiguing Arm-Cycling Exercise in Spinal Muscular Atrophy Types 3 and 4.

J Neuromuscul Dis 2022 ;9(3):397-409

Department of Neurology and Neurosurgery, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands.

Background: Exercise intolerance is an important impairment in patients with SMA, but little is known about the mechanisms underlying this symptom.

Objective: To investigate if reduced motor unit and capillary recruitment capacity in patients with SMA contribute to exercise intolerance.

Methods: Adolescent and adult patients with SMA types 3 and 4 (n = 15) and age- and gender matched controls (n = 15) performed a maximal upper body exercise test. We applied respiratory gas analyses, non-invasive surface electromyography (sEMG) and continuous wave near-infrared spectroscopy (CW-NIRS) to study oxygen consumption, arm muscle motor unit- and capillary recruitment, respectively.

Results: Maximal exercise duration was twofold lower (p < 0.001) and work of breathing and ventilation was 1.6- and 1.8-fold higher (p < 0.05) in patients compared to controls, respectively. Regarding motor unit recruitment, we found higher normalized RMS amplitude onset values of sEMG signals from all muscles and the increase in normalized RMS amplitudes was similar in the m. triceps brachii, m. brachioradialis and m. flexor digitorum in SMA compared to controls. Median frequency, onset values were similar in patients and controls. We found a similar decrease in median frequencies of sEMG recordings from the m. biceps brachii, a diminished decrease from the m. brachioradialis and m. flexor digitorum, but a larger decrease from the m. triceps brachii. With respect to capillary recruitment, CW-NIRS recordings in m. biceps brachii revealed dynamics that were both qualitatively and quantitatively similar in patients and controls.

Conclusion: We found no evidence for the contribution of motor unit and capillary recruitment capacity of the upper arm muscles in adolescent and adult patients with SMA types 3 and 4 as primary limiting factors to premature fatigue during execution of a maximal arm-cycling task.
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http://dx.doi.org/10.3233/JND-210765DOI Listing
May 2022

Multi-parametric quantitative magnetic resonance imaging of the upper arm muscles of patients with spinal muscular atrophy.

NMR Biomed 2022 Jul 14;35(7):e4696. Epub 2022 Feb 14.

UMC Utrecht Brain Center, Department of Neurology and Neurosurgery, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Quantitative magnetic resonance imaging (qMRI) is frequently used to map the disease state and disease progression in the lower extremity muscles of patients with spinal muscular atrophy (SMA). This is in stark contrast to the almost complete lack of data on the upper extremity muscles, which are essential for carrying out daily activities. The aim of this study was therefore to assess the disease state in the upper arm muscles of patients with SMA in comparison with healthy controls by quantitative assessment of fat fraction, diffusion indices, and water T2 relaxation times, and to relate these measures to muscle force. We evaluated 13 patients with SMA and 15 healthy controls with a 3-T MRI protocol consisting of DIXON, diffusion tensor imaging, and T2 sequences. qMRI measures were compared between groups and related to muscle force measured with quantitative myometry. Fat fraction was significantly increased in all upper arm muscles of the patients with SMA compared with healthy controls and correlated negatively with muscle force. Additionally, fat fraction was heterogeneously distributed within the triceps brachii (TB) and brachialis muscle, but not in the biceps brachii muscle. Diffusion indices and water T2 relaxation times were similar between patients with SMA and healthy controls, but we did find a slightly reduced mean diffusivity (MD), λ1, and λ3 in the TB of patients with SMA. Furthermore, MD was positively correlated with muscle force in the TB of patients with SMA. The variation in fat fraction further substantiates the selective vulnerability of muscles. The reduced diffusion tensor imaging indices, along with the positive correlation of MD with muscle force, point to myofiber atrophy. Our results show the feasibility of qMRI to map the disease state in the upper arm muscles of patients with SMA. Longitudinal data in a larger cohort are needed to further explore qMRI to map disease progression and to capture the possible effects of therapeutic interventions.
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http://dx.doi.org/10.1002/nbm.4696DOI Listing
July 2022

Magnetic resonance reveals mitochondrial dysfunction and muscle remodelling in spinal muscular atrophy.

Brain 2022 05;145(4):1422-1435

Centre for Child Development, Exercise and Physical Literacy, Wilhelmina Children's Hospital, University Medical Centre Utrecht, P.O. Box 85090, 3508 AB Utrecht, the Netherlands.

Genetic therapy has changed the prognosis of hereditary proximal spinal muscular atrophy, although treatment efficacy has been variable. There is a clear need for deeper understanding of underlying causes of muscle weakness and exercise intolerance in patients with this disease to further optimize treatment strategies. Animal models suggest that in addition to motor neuron and associated musculature degeneration, intrinsic abnormalities of muscle itself including mitochondrial dysfunction contribute to the disease aetiology. To test this hypothesis in patients, we conducted the first in vivo clinical investigation of muscle bioenergetics. We recruited 15 patients and 15 healthy age and gender-matched control subjects in this cross-sectional clinico-radiological study. MRI and 31P magnetic resonance spectroscopy, the modality of choice to interrogate muscle energetics and phenotypic fibre-type makeup, was performed of the proximal arm musculature in combination with fatiguing arm-cycling exercise and blood lactate testing. We derived bioenergetic parameter estimates including: blood lactate, intramuscular pH and inorganic phosphate accumulation during exercise, and muscle dynamic recovery constants. A linear correlation was used to test for associations between muscle morphological and bioenergetic parameters and clinico-functional measures of muscle weakness. MRI showed significant atrophy of triceps but not biceps muscles in patients. Maximal voluntary contraction force normalized to muscle cross-sectional area for both arm muscles was 1.4-fold lower in patients than in controls, indicating altered intrinsic muscle properties other than atrophy contributed to muscle weakness in this cohort. In vivo31P magnetic resonance spectroscopy identified white-to-red remodelling of residual proximal arm musculature in patients on the basis of altered intramuscular inorganic phosphate accumulation during arm-cycling in red versus white and intermediate myofibres. Blood lactate rise during arm-cycling was blunted in patients and correlated with muscle weakness and phenotypic muscle makeup. Post-exercise metabolic recovery was slower in residual intramuscular white myofibres in patients demonstrating mitochondrial ATP synthetic dysfunction in this particular fibre type. This study provides the first in vivo evidence in patients that degeneration of motor neurons and associated musculature causing atrophy and muscle weakness in 5q spinal muscular atrophy type 3 and 4 is aggravated by disproportionate depletion of myofibres that contract fastest and strongest. Our finding of decreased mitochondrial ATP synthetic function selectively in residual white myofibres provides both a possible clue to understanding the apparent vulnerability of this particular fibre type in 5q spinal muscular atrophy types 3 and 4 as well as a new biomarker and target for therapy.
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http://dx.doi.org/10.1093/brain/awab411DOI Listing
May 2022

Magnetic Resonance-Compatible Arm-Crank Ergometry: A New Platform Linking Whole-Body Calorimetry to Upper-Extremity Biomechanics and Arm Muscle Metabolism.

Front Physiol 2021 19;12:599514. Epub 2021 Feb 19.

Department of Biomedical Sciences of Cells and Systems, Cognitive Neuroscience Center, University Medical Center Groningen, Groningen, Netherlands.

Introduction: Evaluation of the effect of human upper-body training regimens may benefit from knowledge of local energy expenditure in arm muscles. To that end, we developed a novel arm-crank ergometry platform for use in a clinical magnetic resonance (MR) scanner with P spectroscopy capability to study arm muscle energetics. Complementary datasets on heart-rate, whole-body oxygen consumption, proximal arm-muscle electrical activity and power output, were obtained in a mock-up scanner. The utility of the platform was tested by a preliminary study over 4 weeks of skill practice on the efficiency of execution of a dynamic arm-cranking task in healthy subjects.

Results: The new platform successfully recorded the first ever P MR spectra from the human biceps brachii (BB) muscle during dynamic exercise in five healthy subjects. Changes in BB energy- and pH balance varied considerably between individuals. Surface electromyography and mechanical force recordings revealed that individuals employed different arm muscle recruitment strategies, using either predominantly elbow flexor muscles (pull strategy; two subjects), elbow extensor muscles (push strategy; one subject) or a combination of both (two subjects). The magnitude of observed changes in BB energy- and pH balance during ACT execution correlated closely with each strategy. Skill practice improved muscle coordination but did not alter individual strategies. Mechanical efficiency on group level seemed to increase as a result of practice, but the outcomes generated by the new platform showed the additional caution necessary for the interpretation that total energy cost was actually reduced at the same workload.

Conclusion: The presented platform integrates dynamic P MRS recordings from proximal arm muscles with whole-body calorimetry, surface electromyography and biomechanical measurements. This new methodology enables evaluation of cyclic motor performance and outcomes of upper-body training regimens in healthy novices. It may be equally useful for investigations of exercise physiology in lower-limb impaired athletes and wheelchair users as well as frail patients including patients with debilitating muscle disease and the elderly.
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http://dx.doi.org/10.3389/fphys.2021.599514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933461PMC
February 2021

Motor unit reserve capacity in spinal muscular atrophy during fatiguing endurance performance.

Clin Neurophysiol 2021 03 28;132(3):800-807. Epub 2021 Jan 28.

Faculty of Behavioral and Movement Sciences, Vrije Universiteit Amsterdam, Van der Boechorststraat 7, 1081 BT Amsterdam, the Netherlands.

Objective: To investigate the availability of any motor unit reserve capacity during fatiguing endurance testing in patients with spinal muscular atrophy (SMA).

Methods: We recorded surface electromyography (sEMG) of various muscles of upper- and lower extremities of 70 patients with SMA types 2-4 and 19 healthy controls performing endurance shuttle tests (ESTs) of arm and legs. We quantitatively evaluated the development of fatigability and motor unit recruitment using time courses of median frequencies and amplitudes of sEMG signals. Linear mixed effect statistical models were used to evaluate group differences in median frequency and normalized amplitude at onset and its time course.

Results: Normalized sEMG amplitudes at onset of upper body ESTs were significantly higher in patients compared to controls, yet submaximal when related to maximal voluntary contractions, and showed an inverse correlation to SMA phenotype. sEMG median frequencies decreased and amplitudes increased in various muscles during execution of ESTs in patients and controls.

Conclusions: Decreasing median frequencies and increasing amplitudes reveal motor unit reserve capacity in individual SMA patients during ESTs at submaximal performance intensities.

Significance: Preserving, if not expanding motor unit reserve capacity may present a potential therapeutic target in clinical care to reduce fatigability in individual patients with SMA.
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http://dx.doi.org/10.1016/j.clinph.2020.11.044DOI Listing
March 2021

Quantification of Myocardial Creatine and Triglyceride Content in the Human Heart: Precision and Accuracy of in vivo Proton Magnetic Resonance Spectroscopy.

J Magn Reson Imaging 2021 08 10;54(2):411-420. Epub 2021 Feb 10.

Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.

Background: Proton magnetic resonance spectroscopy ( H-MRS) of the human heart is deemed to be a quantitative method to investigate myocardial metabolite content, but thorough validations of in vivo measurements against invasive techniques are lacking.

Purpose: To determine measurement precision and accuracy for quantifications of myocardial total creatine and triglyceride content with localized H-MRS.

Study Type: Test-retest repeatability and measurement validation study.

Subjects: Sixteen volunteers and 22 patients scheduled for open-heart aortic valve replacement or septal myectomy.

Field Strength/sequence: Prospectively ECG-triggered respiratory-gated free-breathing single-voxel point-resolved spectroscopy (PRESS) sequence at 3 T.

Assessment: Myocardial total creatine and triglyceride content were quantified relative to the total water content by fitting the H-MR spectra. Precision was assessed with measurement repeatability. Accuracy was assessed by validating in vivo H-MRS measurements against biochemical assays in myocardial tissue from the same subjects.

Statistical Tests: Intrasession and intersession repeatability was assessed using Bland-Altman analyses. Agreement between H-MRS measurements and biochemical assay was tested with regression analyses.

Results: The intersession repeatability coefficient for myocardial total creatine content was 41.8% with a mean value of 0.083% ± 0.020% of the total water signal, and 36.7% for myocardial triglyceride content with a mean value of 0.35% ± 0.13% of the total water signal. Ex vivo myocardial total creatine concentrations in tissue samples correlated with the in vivo myocardial total creatine content measured with H-MRS: n = 22, r = 0.44; P < 0.05. Likewise, ex vivo myocardial triglyceride concentrations correlated with the in vivo myocardial triglyceride content: n = 20, r = 0.50; P < 0.05.

Data Conclusion: We validated the use of localized H-MRS of the human heart at 3 T for quantitative assessments of in vivo myocardial tissue metabolite content by estimating the measurement precision and accuracy.

Level Of Evidence: 2 TECHNICAL EFFICACY STAGE: 2.
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http://dx.doi.org/10.1002/jmri.27531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277665PMC
August 2021

Effects of acute nutritional ketosis during exercise in adults with glycogen storage disease type IIIa are phenotype-specific: An investigator-initiated, randomized, crossover study.

J Inherit Metab Dis 2021 01 7;44(1):226-239. Epub 2020 Sep 7.

Neuroimaging Center, Department of Neuroscience, University Medical Center Groningen, Groningen, The Netherlands.

Glycogen storage disease type IIIa (GSDIIIa) is an inborn error of carbohydrate metabolism caused by a debranching enzyme deficiency. A subgroup of GSDIIIa patients develops severe myopathy. The purpose of this study was to investigate whether acute nutritional ketosis (ANK) in response to ketone-ester (KE) ingestion is effective to deliver oxidative substrate to exercising muscle in GSDIIIa patients. This was an investigator-initiated, researcher-blinded, randomized, crossover study in six adult GSDIIIa patients. Prior to exercise subjects ingested a carbohydrate drink (~66 g, CHO) or a ketone-ester (395 mg/kg, KE) + carbohydrate drink (30 g, KE + CHO). Subjects performed 15-minute cycling exercise on an upright ergometer followed by 10-minute supine cycling in a magnetic resonance (MR) scanner at two submaximal workloads (30% and 60% of individual maximum, respectively). Blood metabolites, indirect calorimetry data, and in vivo P-MR spectra from quadriceps muscle were collected during exercise. KE + CHO induced ANK in all six subjects with median peak βHB concentration of 2.6 mmol/L (range: 1.6-3.1). Subjects remained normoglycemic in both study arms, but delta glucose concentration was 2-fold lower in the KE + CHO arm. The respiratory exchange ratio did not increase in the KE + CHO arm when workload was doubled in subjects with overt myopathy. In vivo P MR spectra showed a favorable change in quadriceps energetic state during exercise in the KE + CHO arm compared to CHO in subjects with overt myopathy. Effects of ANK during exercise are phenotype-specific in adult GSDIIIa patients. ANK presents a promising therapy in GSDIIIa patients with a severe myopathic phenotype. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT03011203.
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http://dx.doi.org/10.1002/jimd.12302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891643PMC
January 2021

P magnetic resonance spectroscopy in skeletal muscle: Experts' consensus recommendations.

NMR Biomed 2020 Feb 10:e4246. Epub 2020 Feb 10.

Department of Musculoskeletal Biology and Liverpool Magnetic Resonance Imaging Centre (LiMRIC), University of Liverpool, Liverpool, UK.

Skeletal muscle phosphorus-31 P MRS is the oldest MRS methodology to be applied to in vivo metabolic research. The technical requirements of P MRS in skeletal muscle depend on the research question, and to assess those questions requires understanding both the relevant muscle physiology, and how P MRS methods can probe it. Here we consider basic signal-acquisition parameters related to radio frequency excitation, TR, TE, spectral resolution, shim and localisation. We make specific recommendations for studies of resting and exercising muscle, including magnetisation transfer, and for data processing. We summarise the metabolic information that can be quantitatively assessed with P MRS, either measured directly or derived by calculations that depend on particular metabolic models, and we give advice on potential problems of interpretation. We give expected values and tolerable ranges for some measured quantities, and minimum requirements for reporting acquisition parameters and experimental results in publications. Reliable examination depends on a reproducible setup, standardised preconditioning of the subject, and careful control of potential difficulties, and we summarise some important considerations and potential confounders. Our recommendations include the quantification and standardisation of contraction intensity, and how best to account for heterogeneous muscle recruitment. We highlight some pitfalls in the assessment of mitochondrial function by analysis of phosphocreatine (PCr) recovery kinetics. Finally, we outline how complementary techniques (near-infrared spectroscopy, arterial spin labelling, BOLD and various other MRI and H MRS measurements) can help in the physiological/metabolic interpretation of P MRS studies by providing information about blood flow and oxygen delivery/utilisation. Our recommendations will assist in achieving the fullest possible reliable picture of muscle physiology and pathophysiology.
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http://dx.doi.org/10.1002/nbm.4246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243949PMC
February 2020

Nutritional ketosis improves exercise metabolism in patients with very long-chain acyl-CoA dehydrogenase deficiency.

J Inherit Metab Dis 2020 07 5;43(4):787-799. Epub 2020 Feb 5.

Neuroimaging Center, Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, Groningen, The Netherlands.

A maladaptive shift from fat to carbohydrate (CHO) oxidation during exercise is thought to underlie myopathy and exercise-induced rhabdomyolysis in patients with fatty acid oxidation (FAO) disorders. We hypothesised that ingestion of a ketone ester (KE) drink prior to exercise could serve as an alternative oxidative substrate supply to boost muscular ATP homeostasis. To establish a rational basis for therapeutic use of KE supplementation in FAO, we tested this hypothesis in patients deficient in Very Long-Chain acyl-CoA Dehydrogenase (VLCAD). Five patients (range 17-45 y; 4 M/1F) patients were included in an investigator-initiated, randomised, blinded, placebo-controlled, 2-way cross-over study. Patients drank either a KE + CHO mix or an isocaloric CHO equivalent and performed 35 minutes upright cycling followed by 10 minutes supine cycling inside a Magnetic Resonance scanner at individual maximal FAO work rate (fatmax; approximately 40% VO max). The protocol was repeated after a 1-week interval with the alternate drink. Primary outcome measures were quadriceps phosphocreatine (PCr), Pi and pH dynamics during exercise and recovery assayed by in vivo P-MR spectroscopy. Secondary outcomes included plasma and muscle metabolites and respiratory gas exchange recordings. Ingestion of KE rapidly induced mild ketosis and increased muscle BHB content. During exercise at FATMAX, VLCADD-specific plasma acylcarnitine levels, quadriceps glycolytic intermediate levels and in vivo Pi/PCr ratio were all lower in KE + CHO than CHO. These results provide a rational basis for future clinical trials of synthetic ketone ester supplementation therapy in patients with FAO disorders. Trial registration: ClinicalTrials.gov. Protocol ID: NCT03531554; METC2014.492; ABR51222.042.14.
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http://dx.doi.org/10.1002/jimd.12217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384182PMC
July 2020

Doxorubicin-induced skeletal muscle atrophy: Elucidating the underlying molecular pathways.

Acta Physiol (Oxf) 2020 06 31;229(2):e13400. Epub 2019 Oct 31.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Aim: Loss of skeletal muscle mass is a common clinical finding in cancer patients. The purpose of this meta-analysis and systematic review was to quantify the effect of doxorubicin on skeletal muscle and report on the proposed molecular pathways possibly leading to doxorubicin-induced muscle atrophy in both human and animal models.

Methods: A systematic search of the literature was conducted in PubMed, EMBASE, Web of Science and CENTRAL databases. The internal validity of included studies was assessed using SYRCLE's risk of bias tool.

Results: Twenty eligible articles were identified. No human studies were identified as being eligible for inclusion. Doxorubicin significantly reduced skeletal muscle weight (ie EDL, TA, gastrocnemius and soleus) by 14% (95% CI: 9.9; 19.3) and muscle fibre cross-sectional area by 17% (95% CI: 9.0; 26.0) when compared to vehicle controls. Parallel to negative changes in muscle mass, muscle strength was even more decreased in response to doxorubicin administration. This review suggests that mitochondrial dysfunction plays a central role in doxorubicin-induced skeletal muscle atrophy. The increased production of ROS plays a key role within this process. Furthermore, doxorubicin activated all major proteolytic systems (ie calpains, the ubiquitin-proteasome pathway and autophagy) in the skeletal muscle. Although each of these proteolytic pathways contributes to doxorubicin-induced muscle atrophy, the activation of the ubiquitin-proteasome pathway is hypothesized to play a key role. Finally, a limited number of studies found that doxorubicin decreases protein synthesis by a disruption in the insulin signalling pathway.

Conclusion: The results of the meta-analysis show that doxorubicin induces skeletal muscle atrophy in preclinical models. This effect may be explained by various interacting molecular pathways. Results from preclinical studies provide a robust setting to investigate a possible dose-response, separate the effects of doxorubicin from tumour-induced atrophy and to examine underlying molecular pathways. More research is needed to confirm the proposed signalling pathways in humans, paving the way for potential therapeutic approaches.
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http://dx.doi.org/10.1111/apha.13400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317437PMC
June 2020

Failing Homeostasis of Quadriceps Muscle Energy- and pH Balance During Bicycling in a Young Patient With a Fontan Circulation.

Front Cardiovasc Med 2019 21;6:121. Epub 2019 Aug 21.

Division of Neurosciences, Neuroimaging Center, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.

Patients with a congenital heart condition palliated with a Fontan circulation generally present with decreased exercise capacity due to impaired cardiopulmonary function. Recently, a study in patients with a Fontan circulation reported evidence for abnormal vascular endothelial function in leg muscle. We investigated if abnormal skeletal muscle hemodynamics during exercise play a role in the limited exercise tolerance of Fontan patients. If so, abnormalities in intramuscular energy metabolism would be expected both during exercise as well as during post-exercise metabolic recovery. In a young patient with a Fontan circulation and his healthy twin brother we studied the dynamics of energy- and pH-balance in quadriceps muscle during and after a maximal in-magnet bicycling exercise challenge using 31-phosphorus magnetic resonance spectroscopy. An unrelated age-matched boy was also included as independent control. Quadriceps phosphocreatine (PCr) depletion during progressive exercise was more extensive in the Fontan patient than in both controls (95% vs. 80%, respectively). Importantly, it failed to reach an intermittent plateau phase observed in both controls. Quadriceps pH during exercise in the Fontan patient fell 0.3 units at low to moderate workloads, dropping to pH 6.6 at exhaustion. In both controls quadriceps acidification during exercise was absent but for the maximal workload in the twin brother (pH 6.8). Post-exercise, the rate of metabolic recovery in the Fontan patient and both controls was identical (time constant of PCr recovery 32 ± 4, 31 ± 2, and 28 ± 4 s, respectively). Homeostasis of quadriceps energy- and pH-balance during a maximal exercise test failed in the Fontan patient in comparison to his healthy twin brother and an age-matched independent control. Post-exercise metabolic recovery was normal which does not support the contribution of significant endothelial dysfunction affecting adequate delivery of oxidative substrates to the muscle to the lower exercise capacity in this particular Fontan patient. These results suggest that mitochondrial ATP synthetic capacity of the quadriceps muscle was intact but cardiac output to the leg muscles during exercise was insufficient to meet the muscular demand for oxygen. Therefore, improving cardiac output remains the main therapeutic target to improve exercise capacity in patients with a Fontan circulation.
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http://dx.doi.org/10.3389/fcvm.2019.00121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712941PMC
August 2019

Human Cardiac P-MR Spectroscopy at 3 Tesla Cannot Detect Failing Myocardial Energy Homeostasis during Exercise.

Front Physiol 2017 27;8:939. Epub 2017 Nov 27.

Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.

Phosphorus-31 magnetic resonance spectroscopy (P-MRS) is a unique non-invasive imaging modality for probing high-energy phosphate metabolism in the human heart. We investigated whether current P-MRS methodology would allow for clinical applications to detect exercise-induced changes in (patho-)physiological myocardial energy metabolism. Hereto, measurement variability and repeatability of three commonly used localized P-MRS methods [3D image-selected spectroscopy (ISIS) and 1D ISIS with 1D chemical shift imaging (CSI) oriented either perpendicular or parallel to the surface coil] to quantify the myocardial phosphocreatine (PCr) to adenosine triphosphate (ATP) ratio in healthy humans ( = 8) at rest were determined on a clinical 3 Tesla MR system. Numerical simulations of myocardial energy homeostasis in response to increased cardiac work rates were performed using a biophysical model of myocardial oxidative metabolism. Hypertrophic cardiomyopathy was modeled by either inefficient sarcomere ATP utilization or decreased mitochondrial ATP synthesis. The effect of creatine depletion on myocardial energy homeostasis was explored for both conditions. The mean myocardial PCr/ATP ratio measured with 3D ISIS was 1.57 ± 0.17 with a large repeatability coefficient of 40.4%. For 1D CSI in a 1D ISIS-selected slice perpendicular to the surface coil, the PCr/ATP ratio was 2.78 ± 0.50 (repeatability 42.5%). With 1D CSI in a 1D ISIS-selected slice parallel to the surface coil, the PCr/ATP ratio was 1.70 ± 0.56 (repeatability 43.7%). The model predicted a PCr/ATP ratio reduction of only 10% at the maximal cardiac work rate in normal myocardium. Hypertrophic cardiomyopathy led to lower PCr/ATP ratios for high cardiac work rates, which was exacerbated by creatine depletion. Simulations illustrated that when conducting cardiac P-MRS exercise stress testing with large measurement error margins, results obtained under pathophysiologic conditions may still lie well within the 95% confidence interval of normal myocardial PCr/ATP dynamics. Current measurement precision of localized P-MRS for quantification of the myocardial PCr/ATP ratio precludes the detection of the changes predicted by computational modeling. This hampers clinical employment of P-MRS for diagnostic testing and risk stratification, and warrants developments in cardiac P-MRS exercise stress testing methodology.
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http://dx.doi.org/10.3389/fphys.2017.00939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5712006PMC
November 2017

Improving the physiological realism of experimental models.

Interface Focus 2016 Apr;6(2):20150076

Neuroimaging Centre, Division of Neuroscience, University Medical Center Groningen, Groningen, The Netherlands; Department of Radiology, Academic Medical Center Amsterdam, University of Amsterdam, Amsterdam, The Netherlands.

The Virtual Physiological Human (VPH) project aims to develop integrative, explanatory and predictive computational models (C-Models) as numerical investigational tools to study disease, identify and design effective therapies and provide an in silico platform for drug screening. Ultimately, these models rely on the analysis and integration of experimental data. As such, the success of VPH depends on the availability of physiologically realistic experimental models (E-Models) of human organ function that can be parametrized to test the numerical models. Here, the current state of suitable E-models, ranging from in vitro non-human cell organelles to in vivo human organ systems, is discussed. Specifically, challenges and recent progress in improving the physiological realism of E-models that may benefit the VPH project are highlighted and discussed using examples from the field of research on cardiovascular disease, musculoskeletal disorders, diabetes and Parkinson's disease.
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http://dx.doi.org/10.1098/rsfs.2015.0076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4759746PMC
April 2016

Muscle Metabolic Responses During Dynamic In-Magnet Exercise Testing: A Pilot Study in Children with an Idiopathic Inflammatory Myopathy.

Acad Radiol 2015 Nov 8;22(11):1443-8. Epub 2015 Aug 8.

Division of Pediatrics, Child Development and Exercise Center, Wilhelmina Children's Hospital, University Medical Center Utrecht, Rm KB.02.056.0, P.O. Box 85090, NL-3508 AB Utrecht, The Netherlands; Neuroimaging Center, Department of Neuroscience, University Medical Center Groningen, Groningen, The Netherlands.

Rationale And Objectives: The clinical utility of supine in-magnet bicycling in combination with phosphorus magnetic resonance spectroscopy ((31)P MRS) to evaluate quadriceps muscle metabolism was examined in four children with juvenile dermatomyositis (JDM) in remission and healthy age- and gender-matched controls.

Materials And Methods: Two identical maximal supine bicycling tests were performed using a magnetic resonance-compatible ergometer. During the first test, cardiopulmonary performance was established in the exercise laboratory. During the second test, quadriceps energy balance and acid/base balance during incremental exercise and phosphocreatine recovery were determined using (31)P MRS.

Results: During the first test, no significant differences were found between patients with JDM and their healthy peers regarding cardiopulmonary performance. The outcomes of the first test indicate that both groups attained maximal performance. During the second test, quadriceps phosphocreatine and pH time courses were similar in all but one patient experiencing idiopathic postexercise pain. This patient demonstrated faster phosphocreatine depletion and acidification during exercise, yet postexercise mitochondrial adenosine triphosphate synthesis rate measured by phosphocreatine recovery kinetics was approximately twofold faster than control (time constant 23 seconds vs 43 ± 7 seconds, respectively).

Conclusions: These results highlight the utility of in-magnet cycle ergometry in combination with (31)P MRS to assess and monitor muscle energetic patterns in pediatric patients with inflammatory myopathies.
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http://dx.doi.org/10.1016/j.acra.2015.06.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5449456PMC
November 2015

31P MR spectroscopy and computational modeling identify a direct relation between Pi content of an alkaline compartment in resting muscle and phosphocreatine resynthesis kinetics in active muscle in humans.

PLoS One 2013 30;8(9):e76628. Epub 2013 Sep 30.

Department of Radiology, University Medical Center Utrecht, Utrecht, The Netherlands.

The assessment of mitochondrial properties in skeletal muscle is important in clinical research, for instance in the study of diabetes. The gold standard to measure mitochondrial capacity non-invasively is the phosphocreatine (PCr) recovery rate after exercise, measured by (31)P Magnetic Resonance spectroscopy ((31)P MRS). Here, we sought to expand the evidence base for an alternative method to assess mitochondrial properties which uses (31)P MRS measurement of the Pi content of an alkaline compartment attributed to mitochondria (Pi2; as opposed to cytosolic Pi (Pi1)) in resting muscle at high magnetic field. Specifically, the PCr recovery rate in human quadriceps muscle was compared with the signal intensity of the Pi2 peak in subjects with varying mitochondrial content of the quadriceps muscle as a result of athletic training, and the results were entered into a mechanistic computational model of mitochondrial metabolism in muscle to test if the empirical relation between Pi2/Pi1 ratio and the PCr recovery was consistent with theory. Localized (31)P spectra were obtained at 7T from resting vastus lateralis muscle to measure the intensity of the Pi2 peak. In the endurance trained athletes a Pi2/Pi1 ratio of 0.07 ± 0.01 was found, compared to a significantly lower (p<0.05) Pi2/Pi1 ratio of 0.03 ± 0.01 in the normally active group. Next, PCr recovery kinetics after in magnet bicycle exercise were measured at 1.5T. For the endurance trained athletes, a time constant τPCr 12 ± 3 s was found, compared to 24 ± 5s in normally active subjects. Without any parameter optimization the computational model prediction matched the experimental data well (r(2) of 0.75). Taken together, these results suggest that the Pi2 resonance in resting human skeletal muscle observed at 7T provides a quantitative MR-based functional measure of mitochondrial density.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0076628PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3786961PMC
June 2014

Prediction of muscle energy states at low metabolic rates requires feedback control of mitochondrial respiratory chain activity by inorganic phosphate.

PLoS One 2012 28;7(3):e34118. Epub 2012 Mar 28.

BioModeling and Bioinformatics, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.

The regulation of the 100-fold dynamic range of mitochondrial ATP synthesis flux in skeletal muscle was investigated. Hypotheses of key control mechanisms were included in a biophysical model of oxidative phosphorylation and tested against metabolite dynamics recorded by (31)P nuclear magnetic resonance spectroscopy ((31)P MRS). Simulations of the initial model featuring only ADP and Pi feedback control of flux failed in reproducing the experimentally sampled relation between myoplasmic free energy of ATP hydrolysis (ΔG(p) = ΔG(p)(o')+RT ln ([ADP][Pi]/[ATP]) and the rate of mitochondrial ATP synthesis at low fluxes (<0.2 mM/s). Model analyses including Monte Carlo simulation approaches and metabolic control analysis (MCA) showed that this problem could not be amended by model re-parameterization, but instead required reformulation of ADP and Pi feedback control or introduction of additional control mechanisms (feed forward activation), specifically at respiratory Complex III. Both hypotheses were implemented and tested against time course data of phosphocreatine (PCr), Pi and ATP dynamics during post-exercise recovery and validation data obtained by (31)P MRS of sedentary subjects and track athletes. The results rejected the hypothesis of regulation by feed forward activation. Instead, it was concluded that feedback control of respiratory chain complexes by inorganic phosphate is essential to explain the regulation of mitochondrial ATP synthesis flux in skeletal muscle throughout its full dynamic range.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0034118PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3314597PMC
August 2012

Computational modeling of mitochondrial energy transduction.

Crit Rev Biomed Eng 2011 ;39(5):363-77

Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands.

Mitochondria are the power plant of the heart, burning fat and sugars to supply the muscle with the adenosine triphosphate (ATP) free energy that drives contraction and relaxation during each heart beat. This function was first captured in a mathematical model in 1967. Today, interest in such a model has been rekindled by ongoing in silico integrative physiology efforts such as the Cardiac Physiome project. Here, the status of the field of computational modeling of mitochondrial ATP synthetic function is reviewed.
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http://dx.doi.org/10.1615/critrevbiomedeng.v39.i5.20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4051289PMC
April 2012

Similar mitochondrial activation kinetics in wild-type and creatine kinase-deficient fast-twitch muscle indicate significant Pi control of respiration.

Am J Physiol Regul Integr Comp Physiol 2011 Jun 30;300(6):R1316-25. Epub 2011 Mar 30.

Biomedical NMR, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.

Past simulations of oxidative ATP metabolism in skeletal muscle have predicted that elimination of the creatine kinase (CK) reaction should result in dramatically faster oxygen consumption dynamics during transitions in ATP turnover rate. This hypothesis was investigated. Oxygen consumption of fast-twitch (FT) muscle isolated from wild-type (WT) and transgenic mice deficient in the myoplasmic (M) and mitochondrial (Mi) CK isoforms (MiM CK(-/-)) were measured at 20°C at rest and during electrical stimulation. MiM CK(-/-) muscle oxygen consumption activation kinetics during a step change in contraction rate were 30% faster than WT (time constant 53 ± 3 vs. 69 ± 4 s, respectively; mean ± SE, n = 8 and 6, respectively). MiM CK(-/-) muscle oxygen consumption deactivation kinetics were 380% faster than WT (time constant 74 ± 4 s vs. 264 ± 4 s, respectively). Next, the experiments were simulated using a computational model of the oxidative ATP metabolic network in FT muscle featuring ADP and Pi feedback control of mitochondrial respiration (J. A. L. Jeneson, J. P. Schmitz, N. A. van den Broek, N. A. van Riel, P. A. Hilbers, K. Nicolay, J. J. Prompers. Am J Physiol Endocrinol Metab 297: E774-E784, 2009) that was reparameterized for 20°C. Elimination of Pi control via clamping of the mitochondrial Pi concentration at 10 mM reproduced past simulation results of dramatically faster kinetics in CK(-/-) muscle, while inclusion of Pi control qualitatively explained the experimental observations. On this basis, it was concluded that previous studies of the CK-deficient FT muscle phenotype underestimated the contribution of Pi to mitochondrial respiratory control.
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http://dx.doi.org/10.1152/ajpregu.00204.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3119146PMC
June 2011

Systems biology from micro-organisms to human metabolic diseases: the role of detailed kinetic models.

Biochem Soc Trans 2010 Oct;38(5):1294-301

Department of Liver, Digestive and Metabolic Diseases, University Medical Centre Groningen, University of Groningen, The Netherlands.

Human metabolic diseases are typically network diseases. This holds not only for multifactorial diseases, such as metabolic syndrome or Type 2 diabetes, but even when a single gene defect is the primary cause, where the adaptive response of the entire network determines the severity of disease. The latter may differ between individuals carrying the same mutation. Understanding the adaptive responses of human metabolism naturally requires a systems biology approach. Modelling of metabolic pathways in micro-organisms and some mammalian tissues has yielded many insights, qualitative as well as quantitative, into their control and regulation. Yet, even for a well-known pathway such as glycolysis, precise predictions of metabolite dynamics from experimentally determined enzyme kinetics have been only moderately successful. In the present review, we compare kinetic models of glycolysis in three cell types (African trypanosomes, yeast and skeletal muscle), evaluate their predictive power and identify limitations in our understanding. Although each of these models has its own merits and shortcomings, they also share common features. For example, in each case independently measured enzyme kinetic parameters were used as input. Based on these 'lessons from glycolysis', we will discuss how to make best use of kinetic computer models to advance our understanding of human metabolic diseases.
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http://dx.doi.org/10.1042/BST0381294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3298031PMC
October 2010

An MR-compatible bicycle ergometer for in-magnet whole-body human exercise testing.

Magn Reson Med 2010 Jan;63(1):257-61

Biomedical NMR, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands.

An MR-compatible ergometer was developed for in-magnet whole-body human exercise testing. Designed on the basis of conventional mechanically braked bicycle ergometers and constructed from nonferrous materials, the ergometer was implemented on a 1.5-T whole-body MR scanner. A spectrometer interface was constructed using standard scanner hardware, complemented with custom-built parts and software to enable gated data acquisition during exercise. High-quality 31P NMR spectra were reproducibly obtained from the medial head of the quadriceps muscle of the right leg of eight healthy subjects during two-legged high-frequency pedaling (80 revolutions per minute) at three incremental workloads, including maximal. Muscle phosphocreatine content dropped 82%, from 32.2+/-1.0 mM at rest to 5.7+/-1.1 mM at maximal workload (mean+/-standard error; n=8), indicating that the majority of quadriceps motor units were recruited. The cardiovascular load of the exercise was likewise significant, as evidenced by heart rates of 150 (+/-10%) beats per minute, measured immediately afterward. As such, the newly developed MR bicycling exercise equipment offers a powerful new tool for clinical musculoskeletal and cardiovascular MR investigation. The basic design of the ergometer is highly generic and adaptable for application on a wide selection of whole-body MR scanners.
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http://dx.doi.org/10.1002/mrm.22179DOI Listing
January 2010

Silencing of glycolysis in muscle: experimental observation and numerical analysis.

Exp Physiol 2010 Feb 2;95(2):380-97. Epub 2009 Oct 2.

BioModeling and BioInformatics Group, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.

The longstanding problem of rapid inactivation of the glycolytic pathway in skeletal muscle after contraction was investigated using (31)P NMR spectroscopy and computational modelling. Accumulation of phosphorylated glycolytic intermediates (hexose monophosphates) during cyclic contraction and subsequent turnover during metabolic recovery was measured in vivo in human quadriceps muscle using dynamic (31)P NMR spectroscopy. The concentration of hexose monophosphates in muscle peaked 40 s into metabolic recovery from maximal contractile work at 6.9 +/- 1.3 mm (mean +/- s.d.; n = 8) and subsequently declined at a rate of 0.009 +/- 0.001 mm s(1). It was next tested whether the current knowledge of the kinetic controls in the glycolytic pathway in muscle integrated in the Lambeth and Kushmerick computational model of skeletal muscle glycolysis explained the experimental data. It was found that the model underestimated the magnitude of deactivation of the glycolytic pathway in resting muscle, resulting in depletion of glycolytic intermediates and substrate for oxidative ATP synthesis. Numerical analysis of the model identified phosphofructokinase and pyruvate kinase as the kinetic control sites involved in deactivation of the glycolytic pathway. Ancillary 100-fold inhibition of both phosphofructokinase and pyruvate kinase was found necessary to predict glycolytic intermediate and ADP concentrations correctly in resting human muscle. Incorporation of this information into the model resulted in highly improved agreement between predicted and measured in vivo dynamics of hexose monophosphates in muscle following contraction. We concluded that silencing of the glycolytic pathway in muscle following contraction is most likely to be mediated by phosphofructokinase and pyruvate kinase inactivation on a time scale of seconds and minutes, respectively, and is necessary to prevent depletion of vital cellular substrates.
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http://dx.doi.org/10.1113/expphysiol.2009.049841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2893886PMC
February 2010

Magnitude and control of mitochondrial sensitivity to ADP.

Am J Physiol Endocrinol Metab 2009 Sep 21;297(3):E774-84. Epub 2009 Jul 21.

Biomedical NMR, Dept. of Biomedical Engineering, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands.

The transduction function for ADP stimulation of mitochondrial ATP synthesis in skeletal muscle was reconstructed in vivo and in silico to investigate the magnitude and origin of mitochondrial sensitivity to cytoplasmic ADP concentration changes. Dynamic in vivo measurements of human leg muscle phosphocreatine (PCr) content during metabolic recovery from contractions were performed by (31)P-NMR spectroscopy. The cytoplasmic ADP concentration ([ADP]) and rate of oxidative ATP synthesis (Jp) at each time point were calculated from creatine kinase equilibrium and the derivative of a monoexponential fit to the PCr recovery data, respectively. Reconstructed [ADP]-Jp relations for individual muscles containing more than 100 data points were kinetically characterized by nonlinear curve fitting yielding an apparent kinetic order and ADP affinity of 1.9 +/- 0.2 and 0.022 +/- 0.003 mM, respectively (means +/- SD; n = 6). Next, in silico [ADP]-Jp relations for skeletal muscle were generated using a computational model of muscle oxidative ATP metabolism whereby model parameters corresponding to mitochondrial enzymes were randomly changed by 50-150% to determine control of mitochondrial ADP sensitivity. The multiparametric sensitivity analysis showed that mitochondrial ADP ultrasensitivity is an emergent property of the integrated mitochondrial enzyme network controlled primarily by kinetic properties of the adenine nucleotide translocator.
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http://dx.doi.org/10.1152/ajpendo.00370.2009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3833997PMC
September 2009

Dynamic MRS and MRI of skeletal muscle function and biomechanics.

NMR Biomed 2006 Nov;19(7):927-53

Biomedical NMR, Department of Biomedical Engineering, Eindhoven University of Technology, The Netherlands.

MR is a powerful technique for studying the biomechanical and functional properties of skeletal muscle in vivo in health and disease. This review focuses on 31P, 1H and 13C MR spectroscopy for assessment of the dynamics of muscle metabolism and on dynamic 1H MRI methods for non-invasive measurement of the biomechanical and functional properties of skeletal muscle. The information thus obtained ranges from the microscopic level of the metabolism of the myocyte to the macroscopic level of the contractile function of muscle complexes. The MR technology presented plays a vital role in achieving a better understanding of many basic aspects of muscle function, including the regulation of mitochondrial activity and the intricate interplay between muscle fiber organization and contractile function. In addition, these tools are increasingly being employed to establish novel diagnostic procedures as well as to monitor the effects of therapeutic and lifestyle interventions for muscle disorders that have an increasing impact in modern society.
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http://dx.doi.org/10.1002/nbm.1095DOI Listing
November 2006

Oxidative ATP synthesis in skeletal muscle is controlled by substrate feedback.

Am J Physiol Cell Physiol 2007 Jan 12;292(1):C115-24. Epub 2006 Jul 12.

Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.

Data from (31)P-nuclear magnetic resonance spectroscopy of human forearm flexor muscle were analyzed based on a previously developed model of mitochondrial oxidative phosphorylation (PLoS Comp Bio 1: e36, 2005) to test the hypothesis that substrate level (concentrations of ADP and inorganic phosphate) represents the primary signal governing the rate of mitochondrial ATP synthesis and maintaining the cellular ATP hydrolysis potential in skeletal muscle. Model-based predictions of cytoplasmic concentrations of phosphate metabolites (ATP, ADP, and P(i)) matched data obtained from 20 healthy volunteers and indicated that as work rate is varied from rest to submaximal exercise commensurate increases in the rate of mitochondrial ATP synthesis are effected by changes in concentrations of available ADP and P(i). Additional data from patients with a defect of complex I of the respiratory chain and a patient with a deficiency in the mitochondrial adenine nucleotide translocase were also predicted the by the model by making the appropriate adjustments to the activities of the affected proteins associates with the defects, providing both further validation of the biophysical model of the control of oxidative phosphorylation and insight into the impact of these diseases on the ability of the cell to maintain its energetic state.
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http://dx.doi.org/10.1152/ajpcell.00237.2006DOI Listing
January 2007

Increased resistance to fatigue in creatine kinase deficient muscle is not due to improved contractile economy.

Pflugers Arch 2006 Jun 11;452(3):342-8. Epub 2006 Mar 11.

Department of Experimental In Vivo NMR, Image Sciences Institute, University Medical Center Utrecht, Utrecht, The Netherlands.

There has been speculation on the origin of the increased endurance of skeletal muscles in creatine kinase (CK)-deficient mice. Important factors that have been raised include the documented increased mitochondrial capacity and alterations in myosin heavy chain (MyHC) isoform composition in CK-deficient muscle. More recently, the absence of inorganic phosphate release from phosphocreatine hydrolysis in exercising CK-deficient muscle has been postulated to contribute to the lower fatigueability in skeletal muscle. In this study, we tested the hypothesis that the reported shift in MyHC composition to slower isoforms in CK-deficient muscle leads to a decrease in oxygen cost of twitch performance. To that aim, extensor digitorum longus (EDL) and soleus (SOL) muscles were isolated from wild-type (WT) and knock-out mice deficient in the cytoplasmic muscle-type and sarcomeric mitochondrial isoenzymes of CK, and oxygen consumption per twitch time-tension-integral (TTI) was measured. The results show that the adaptive response to loss of CK function does not involve any major change to contractile economy of skeletal muscle.
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http://dx.doi.org/10.1007/s00424-005-0041-6DOI Listing
June 2006

Mitochondrial affinity for ADP is twofold lower in creatine kinase knock-out muscles. Possible role in rescuing cellular energy homeostasis.

FEBS J 2005 Feb;272(4):956-65

Department of Experimental In Vivo NMR, Image Sciences Institute, University Medical Center, Utrecht, the Netherlands.

Adaptations of the kinetic properties of mitochondria in striated muscle lacking cytosolic (M) and/or mitochondrial (Mi) creatine kinase (CK) isoforms in comparison to wild-type (WT) were investigated in vitro. Intact mitochondria were isolated from heart and gastrocnemius muscle of WT and single- and double CK-knock-out mice strains (cytosolic (M-CK-/-), mitochondrial (Mi-CK-/-) and double knock-out (MiM-CK-/-), respectively). Maximal ADP-stimulated oxygen consumption flux (State3 Vmax; nmol O2 x mg mitochondrial protein(-1) x min(-1)) and ADP affinity (K50ADP; microM) were determined by respirometry. State 3 Vmax and of M-CK-/- and MiM-CK-/- gastrocnemius mitochondria were twofold higher than those of WT, but were unchanged for Mi-CK-/-. For mutant cardiac mitochondria, only the of mitochondria isolated from the MiM-CK-/- phenotype was different (i.e. twofold higher) than that of WT. The implications of these adaptations for striated muscle function were explored by constructing force-flow relations of skeletal muscle respiration. It was found that the identified shift in affinity towards higher ADP concentrations in MiM-CK-/- muscle genotypes may contribute to linear mitochondrial control of the reduced cytosolic ATP free energy potentials in these phenotypes.
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http://dx.doi.org/10.1111/j.1742-4658.2004.04529.xDOI Listing
February 2005
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