Endurance training and hydroxyurea have synergistic effects on muscle function and energetics in sickle cell disease mice.

Sickle cell disease (SCD) is an hemoglobinopathy resulting in the production of an abnormal Hb (HbS) which can polymerize in deoxygenated conditions, leading to the sickling of red blood cells (RBC). These alterations can decrease the oxygen-carrying capacity leading to impaired function and energetics of skeletal muscle. Any strategy which could reverse the corresponding defects could be of interest. In SCD, endurance training is known to improve multiples muscle properties which restores patient's exercise capacity but present reduced effects in anemic patients. Hydroxyurea (HU) can increase fetal hemoglobin production which can reduce anemia in patients. The present study was conducted to determine whether HU can improve the effects of endurance training to improve muscle function and energetics. Twenty SCD Townes mice have been trained for 8 weeks with (n = 11) or without (n = 9) HU. SCD mice muscle function and energetics were analyzed during a standardized rest-exercise-recovery protocol, using Phosphorus-31 Magnetic resonance spectroscopy (31P-MRS) and transcutaneous stimulation. The combination of training and HU specifically decreased fatigue index and PCr consumption while muscle oxidative capacity was improved. These results illustrate the potential synergistic effects of endurance training and HU on muscle function and energetics in sickle cell disease.

Interhemispheric reactivity of the subthalamic nucleus sustains progressive dopamine neuron loss in asymmetrical parkinsonism.

Parkinson's disease (PD) is characterized by the progressive and asymmetrical degeneration of the nigrostriatal dopamine neurons and the unilateral presentation of the motor symptoms at onset, contralateral to the most impaired hemisphere. We previously developed a rat PD model that mimics these typical features, based on unilateral injection of a substrate inhibitor of excitatory amino acid transporters, L-trans-pyrrolidine-2,4-dicarboxylate (PDC), in the substantia nigra (SN). Here, we used this progressive model in a multilevel study (behavioral testing, in vivo 1H-magnetic resonance spectroscopy, slice electrophysiology, immunocytochemistry and in situ hybridization) to characterize the functional changes occurring in the cortico-basal ganglia-cortical network in an evolving asymmetrical neurodegeneration context and their possible contribution to the cell death progression. We focused on the corticostriatal input and the subthalamic nucleus (STN), two glutamate components with major implications in PD pathophysiology. In the striatum, glutamate and glutamine levels increased from presymptomatic stages in the PDC-injected hemisphere only, which also showed enhanced glutamatergic transmission and loss of plasticity at corticostriatal synapses assessed at symptomatic stage. Surprisingly, the contralateral STN showed earlier and stronger reactivity than the ipsilateral side (increased intraneuronal cytochrome oxidase subunit I mRNA levels; enhanced glutamate and glutamine concentrations). Moreover, its lesion at early presymptomatic stage halted the ongoing neurodegeneration in the PDC-injected SN and prevented the expression of motor asymmetry. These findings reveal the existence of endogenous interhemispheric processes linking the primary injured SN and the contralateral STN that could sustain progressive dopamine neuron loss, opening new perspectives for disease-modifying treatment of PD.

The Impact of Fatty Infiltration on MRI Segmentation of Lower Limb Muscles in Neuromuscular Diseases: A Comparative Study of Deep Learning Approaches.

BACKGROUND: Deep learning methods have been shown to be useful for segmentation of lower limb muscle MRIs of healthy subjects but, have not been sufficiently evaluated on neuromuscular disease (NDM) patients. PURPOSE: Evaluate the influence of fat infiltration on convolutional neural network (CNN) segmentation of MRIs from NMD patients. STUDY TYPE: Retrospective study. SUBJECTS: Data were collected from a hospital database of 67 patients with NMDs and 14 controls (age: 53 ± 17 years, sex: 48 M, 33 F). Ten individual muscles were segmented from the thigh and six from the calf (20 slices, 200 cm section). FIELD STRENGTH/SEQUENCE: A 1.5 T. Sequences: 2D T1 -weighted fast spin echo. Fat fraction (FF): three-point Dixon 3D GRE, magnetization transfer ratio (MTR): 3D MT-prepared GRE, T2: 2D multispin-echo sequence. ASSESSMENT: U-Net 2D, U-Net 3D, TransUNet, and HRNet were trained to segment thigh and leg muscles (101/11 and 95/11 training/validation images, 10-fold cross-validation). Automatic and manual segmentations were compared based on geometric criteria (Dice coefficient [DSC], outlier rate, absence rate) and reliability of measured MRI quantities (FF, MTR, T2, volume). STATISTICAL TESTS: Bland-Altman plots were chosen to describe agreement between manual vs. automatic estimated FF, MTR, T2 and volume. Comparisons were made between muscle populations with an FF greater than 20% (G20+) and lower than 20% (G20-). RESULTS: The CNNs achieved equivalent results, yet only HRNet recognized every muscle in the database, with a DSC of 0.91 ± 0.08, and measurement biases reaching -0.32% ± 0.92% for FF, 0.19 ± 0.77 for MTR, -0.55 ± 1.95 msec for T2, and - 0.38 ± 3.67 cm3 for volume. The performances of HRNet, between G20- and G20+ decreased significantly. DATA CONCLUSION: HRNet was the most appropriate network, as it did not omit any muscle. The accuracy obtained shows that CNNs could provide fully automated methods for studying NMDs. However, the accuracy of the methods may be degraded on the most infiltrated muscles (>20%). EVIDENCE LEVEL: 4. TECHNICAL EFFICACY: Stage 1.

Estimation of subvoxel fat infiltration in neurodegenerative muscle disorders using quantitative multi-T2 analysis.

MRI's T2 relaxation time is a valuable biomarker for neuromuscular disorders and muscle dystrophies. One of the hallmarks of these pathologies is the infiltration of adipose tissue and a loss of muscle volume. This leads to a mixture of two signal components, from fat and from water, to appear in each imaged voxel, each having a specific T2 relaxation time. In this proof-of-concept work, we present a technique that can separate the signals from water and from fat within each voxel, measure their separate T2 values, and calculate their relative fractions. The echo modulation curve (EMC) algorithm is a dictionary-based technique that offers accurate and reproducible mapping of T2 relaxation times. We present an extension of the EMC algorithm for estimating subvoxel fat and water fractions, alongside the T2 and proton-density values of each component. To facilitate data processing, calf and thigh anatomy were automatically segmented using a fully convolutional neural network and FSLeyes software. The preprocessing included creating two signal dictionaries, for water and for fat, using Bloch simulations of the prospective protocol. Postprocessing included voxelwise fitting for two components, by matching the experimental decay curve to a linear combination of the two simulated dictionaries. Subvoxel fat and water fractions and relaxation times were generated and used to calculate a new quantitative biomarker, termed viable muscle index, and reflecting disease severity. This biomarker indicates the fraction of remaining muscle out of the entire muscle region. The results were compared with those using the conventional Dixon technique, showing high agreement (R = 0.98, p < 0.001). It was concluded that the new extension of the EMC algorithm can be used to quantify abnormal fat infiltration as well as identify early inflammatory processes corresponding to elevation in the T2 value of the water (muscle) component. This new ability may improve the diagnostic accuracy of neuromuscular diseases, help stratification of patients according to disease severity, and offer an efficient tool for tracking disease progression.

Effects of hydroxyurea on skeletal muscle energetics and force production in a sickle cell disease murine model.

Hydroxyurea (HU) is commonly used as a treatment for patients with sickle cell disease (SCD) to enhance fetal hemoglobin production. This increased production is expected to reduce anemia (which depresses oxygen transport) and abnormal Hb content alleviating clinical symptoms such as vaso-occlusive crisis and acute chest syndrome. The effects of HU on skeletal muscle bioenergetics in vivo are still unknown. Due to the beneficial effects of HU upon oxygen delivery, improved skeletal muscle energetics and function in response to a HU treatment have been hypothesized. Muscle energetics and function were analyzed during a standardized rest-exercise-recovery protocol, using 31P-magnetic resonance spectroscopy in Townes SCD mice. Measurements were performed in three groups of mice: one group of 2-mo-old mice (SCD2m, n = 8), another one of 4-mo-old mice (SCD4m, n = 8), and a last group of 4-mo-old mice that have been treated from 2 mo of age with HU at 50 mg/kg/day (SCD4m-HU, n = 8). As compared with SCD2m mice, SCD4m mice were heavier and displayed a lower acidosis. As lower specific forces were developed by SCD4m compared with SCD2m, greater force-normalized phosphocreatine consumption and oxidative and nonoxidative costs of contraction were also reported. HU-treated mice (SCD4m-HU) displayed a significantly higher specific force production as compared with untreated mice (SCD4m), whereas muscle energetics was unchanged. Overall, our results support a beneficial effect of HU on muscle function.NEW & NOTEWORTHY Our results highlighted that force production decreases between 2 and 4 mo of age in SCD mice thereby indicating a decrease of muscle function during this period. Of interest, HU treatment seemed to blunt the observed age effect given that SCD4m-HU mice displayed a higher specific force production as compared with SCD4m mice. In that respect, HU treatment would help to maintain a higher capacity of force production during aging in SCD.

Effects of Hydroxyurea on Skeletal Muscle Energetics and Function in a Mildly Anemic Mouse Model.

Hydroxyurea (HU) is a ribonucleotide reductase inhibitor most commonly used as a therapeutic agent in sickle cell disease (SCD) with the aim of reducing the risk of vaso-occlusion and improving oxygen transport to tissues. Previous studies suggest that HU may be even beneficial in mild anemia. However, the corresponding effects on skeletal muscle energetics and function have never been reported in such a mild anemia model. Seventeen mildly anemic HbAA Townes mice were subjected to a standardized rest-stimulation (transcutaneous stimulation)-protocol while muscle energetics using 31Phosphorus magnetic resonance spectroscopy and muscle force production were assessed and recorded. Eight mice were supplemented with hydroxyurea (HU) for 6 weeks while 9 were not (CON). HU mice displayed a higher specific total force production compared to the CON, with 501.35 ± 54.12 N/mm3 and 437.43 ± 57.10 N/mm3 respectively (+14.6%, p < 0.05). Neither the total rate of energy consumption nor the oxidative metabolic rate were significantly different between groups. The present results illustrated a positive effect of a HU chronic supplementation on skeletal muscle function in mice with mild anemia.

Respiratory-triggered quantitative MR spectroscopy of the human cervical spinal cord at 7 T.

PURPOSE: Ultra-high field 1 H MR spectroscopy (MRS) is of great interest to help characterizing human spinal cord pathologies. However, very few studies have been reported so far in this small size structure at these fields due to challenging experimental difficulties caused by static and radiofrequency field heterogeneities, as well as physiological motion. In this work, in line with the recent developments proposed to strengthen spinal cord MRS feasibility at 7 T, a respiratory-triggered acquisition approach was optimized to compensate for dynamic B 0 field heterogeneities and to provide robust cervical spinal cord MRS data. METHODS: A semi-LASER sequence was purposely used, and a dedicated raw data processing algorithm was developed to enhance MR spectral quality by discarding corrupted scans. To legitimate the choices done during the optimization stage, additional tests were carried out to determine the impact of breathing, voluntary motion, body mass index, and fitting algorithm. An in-house quantification tool was concomitantly designed for accurate estimation of the metabolite concentration ratios for choline, N-acetyl-aspartate (NAA), myo-inositol and glutathione. The method was tested on a cohort of 14 healthy volunteers. RESULTS: Average water linewidth and NAA signal-to-noise ratio reached 0.04 ppm and 11.01, respectively. The group-average metabolic ratios were in good agreement with previous studies and showed intersession reproducibility variations below 30%. CONCLUSION: The developed approach allows a rise of the acquired MRS signal quality and of the quantification robustness as compared to previous studies hence offering strengthened possibilities to probe the metabolism of degenerative and traumatic spinal cord pathologies.

Skeletal Muscle Mitochondrial Adaptations to Maximal Strength Training in Older Adults.

Maximal strength training (MST) results in robust improvements in skeletal muscle force production, efficiency, and mass. However, the effects of MST on muscle mitochondria are still unknown. Accordingly, the purpose of this study was to examine, from the molecular level to whole-muscle, mitochondrial adaptations induced by 8 weeks of knee-extension MST in the quadriceps of 10 older adults using immunoblotting, spectrophotometry, high-resolution respirometry in permeabilized muscle fibers, in vivo 31P magnetic resonance spectroscopy (31P-MRS), and gas exchange. As anticipated, MST resulted in an increased isometric knee-extensor force from 133 ± 36 to 147 ± 49 Nm (p < .05) and quadriceps muscle volume from 1,410 ± 103 to 1,555 ± 455 cm3 (p < .05). Mitochondrial complex (I-V) protein abundance and citrate synthase activity were not significantly altered by MST. Assessed ex vivo, maximal ADP-stimulated respiration (state 3CI+CII, PRE: 23 ± 6 and POST: 14 ± 5 ρM·mg-1·s-1, p < .05), was decreased by MST, predominantly, as a result of a decline in complex I-linked respiration (p < .05). Additionally, state 3 free-fatty acid linked respiration was decreased following MST (PRE: 19 ± 5 and POST: 14 ± 3 ρM·mg-1·s-1, p < .05). Assessed in vivo, MST slowed the PCr recovery time constant (PRE: 49 ± 13 and POST: 57 ± 16 seconds, p < .05) and lowered, by ~20% (p = .055), the quadriceps peak rate of oxidative ATP synthesis, but did not significantly alter the oxidation of lipid. Although these, likely qualitative, mitochondrial adaptations are potentially negative in terms of skeletal muscle energetic capacity, they need to be considered in light of the many improvements in muscle function that MST affords older adults.

Novel role of Tieg1 in muscle metabolism and mitochondrial oxidative capacities.

AIM: Tieg1 is involved in multiple signalling pathways, human diseases, and is highly expressed in muscle where its functions are poorly understood. METHODS: We have utilized Tieg1 knockout (KO) mice to identify novel and important roles for this transcription factor in regulating muscle ultrastructure, metabolism and mitochondrial functions in the soleus and extensor digitorum longus (EDL) muscles. RNA sequencing, immunoblotting, transmission electron microscopy, MRI, NMR, histochemical and mitochondrial function assays were performed. RESULTS: Loss of Tieg1 expression resulted in altered sarcomere organization and a significant decrease in mitochondrial number. Histochemical analyses demonstrated an absence of succinate dehydrogenase staining and a decrease in cytochrome c oxidase (COX) enzyme activity in KO soleus with similar, but diminished, effects in the EDL. Decreased complex I, COX and citrate synthase (CS) activities were detected in the soleus muscle of KO mice indicating altered mitochondrial function. Complex I activity was also diminished in KO EDL. Significant decreases in CS and respiratory chain complex activities were identified in KO soleus. 1 H-NMR spectra revealed no significant metabolic difference between wild-type and KO muscles. However, 31 P spectra revealed a significant decrease in phosphocreatine and ATPγ. Altered expression of 279 genes, many of which play roles in mitochondrial and muscle function, were identified in KO soleus muscle. Ultimately, all of these changes resulted in an exercise intolerance phenotype in Tieg1 KO mice. CONCLUSION: Our findings have implicated novel roles for Tieg1 in muscle including regulation of gene expression, metabolic activity and organization of tissue ultrastructure. This muscle phenotype resembles diseases associated with exercise intolerance and myopathies of unknown consequence.

Metabolic counterparts of sodium accumulation in multiple sclerosis: A whole brain 23Na-MRI and fast 1H-MRSI study.

BACKGROUND: Increase of brain total sodium concentrations (TSC) is present in multiple sclerosis (MS), but its pathological involvement has not been assessed yet. OBJECTIVE: To determine in vivo the metabolic counterpart of brain sodium accumulation. MATERIALS/METHODS: Whole brain 23Na-MR imaging and 3D-1H-EPSI data were collected in 21 relapsing-remitting multiple sclerosis (RRMS) patients and 20 volunteers. Metabolites and sodium levels were extracted from several regions of grey matter (GM), normal-appearing white matter (NAWM) and white matter (WM) T2 lesions. Metabolic and ionic levels expressed as Z-scores have been averaged over the different compartments and used to explain sodium accumulations through stepwise regression models. RESULTS: MS patients showed significant 23Na accumulations with lower choline and glutamate-glutamine (Glx) levels in GM; 23Na accumulations with lower N-acetyl aspartate (NAA), Glx levels and higher Myo-Inositol (m-Ins) in NAWM; and higher 23Na, m-Ins levels with lower NAA in WM T2 lesions. Regression models showed associations of TSC increase with reduced NAA in GM, NAWM and T2 lesions, as well as higher total-creatine, and smaller decrease of m-Ins in T2 lesions. GM Glx levels were associated with clinical scores. CONCLUSION: Increase of TSC in RRMS is mainly related to neuronal mitochondrial dysfunction while dysfunction of neuro-glial interactions within GM is linked to clinical scores.

Maximal strength training increases muscle force generating capacity and the anaerobic ATP synthesis flux without altering the cost of contraction in elderly.

Aging is associated with a progressive decline in skeletal muscle function, then leading to impaired exercise tolerance. Maximal strength training (MST) appears to be a practical and effective intervention to increase both exercise capacity and efficiency. However, the underlying physiological mechanisms responsible for these functional improvements are still unclear. Accordingly, the purpose of this study was to examine the intramuscular and metabolic adaptations induced by 8 weeks of knee-extension MST in the quadriceps of 10 older individuals (75 ±â€¯9 yrs) by employing a combination of molecular, magnetic resonance 1H-imaging and 31P-spectroscopy, muscle biopsies, motor nerve stimulation, and indirect calorimetry techniques. Dynamic and isometric muscle strength were both significantly increased by MST. The greater torque-time integral during sustained isometric maximal contraction post-MST (P = 0.002) was associated with increased rates of ATP synthesis from anaerobic glycolysis (PRE: 10 ±â€¯7 mM·min-1; POST: 14 ±â€¯7 mM·min-1, P = 0.02) and creatine kinase reaction (PRE: 31 ±â€¯10 mM·min-1; POST: 41 ±â€¯10 mM·min-1, P = 0.006) such that the ATP cost of contraction was not significantly altered. Expression of fast myosin heavy chain, quadriceps muscle volume, and submaximal cycling net efficiency were also increased with MST (P = 0.005; P = 0.03 and P = 0.03, respectively). Overall, MST induced a shift toward a more glycolytic muscle phenotype allowing for greater muscle force production during sustained maximal contraction. Consequently, some of the MST-induced improvements in exercise tolerance might stem from a greater anaerobic capacity to generate ATP, while the improvement in exercise efficiency appears to be independent from an alteration in the ATP cost of contraction.

Oxygen availability and skeletal muscle oxidative capacity in patients with peripheral artery disease: implications from in vivo and in vitro assessments.

Evidence suggests that the peak skeletal muscle mitochondrial ATP synthesis rate ( Vmax) in patients with peripheral artery disease (PAD) may be attenuated due to disease-related impairments in O2 supply. However, in vitro assessments suggest intrinsic deficits in mitochondrial respiration despite ample O2 availability. To address this conundrum, Doppler ultrasound, near-infrared spectroscopy, phosphorus magnetic resonance spectroscopy, and high-resolution respirometry were combined to assess convective O2 delivery, tissue oxygenation, Vmax, and skeletal muscle mitochondrial capacity (complex I + II, state 3 respiration), respectively, in the gastrocnemius muscle of 10 patients with early stage PAD and 11 physical activity-matched healthy control (HC) subjects. All participants were studied in free-flow control conditions (FF) and with reactive hyperemia (RH) induced by a period of brief ischemia during the last 30 s of submaximal plantar flexion exercise. Patients with PAD repeated the FF and RH trials under hyperoxic conditions (FF + 100% O2 and RH + 100% O2). Compared with HC subjects, patients with PAD exhibited attenuated O2 delivery at the same absolute work rate and attenuated tissue reoxygenation and Vmax after relative intensity-matched exercise. Compared with the FF condition, only RH + 100% O2 significantly increased convective O2 delivery (~44%), tissue reoxygenation (~54%), and Vmax (~60%) in patients with PAD ( P < 0.05), such that Vmax was now not different from HC subjects. Furthermore, there was no evidence of an intrinsic mitochondrial deficit in PAD, as assessed in vitro with adequate O2. Thus, in combination, this comprehensive in vivo and in vitro investigation implicates O2 supply as the predominant factor limiting mitochondrial oxidative capacity in early stage PAD. NEW & NOTEWORTHY Currently, there is little accord as to the role of O2 availability and mitochondrial function in the skeletal muscle dysfunction associated with peripheral artery disease. This is the first study to comprehensively use both in vivo and in vitro approaches to document that the skeletal muscle dysfunction associated with early stage peripheral artery disease is predominantly a consequence of limited O2 supply and not the impact of an intrinsic mitochondrial defect in this pathology.

Muscle MRI in patients with dysferlinopathy: pattern recognition and implications for clinical trials.

BACKGROUND AND OBJECTIVE: Dysferlinopathies are a group of muscle disorders caused by mutations in the DYSF gene. Previous muscle imaging studies describe a selective pattern of muscle involvement in smaller patient cohorts, but a large imaging study across the entire spectrum of the dysferlinopathies had not been performed and previous imaging findings were not correlated with functional tests. METHODS: We present cross-sectional T1-weighted muscle MRI data from 182 patients with genetically confirmed dysferlinopathies. We have analysed the pattern of muscles involved in the disease using hierarchical analysis and presented it as heatmaps. Results of the MRI scans have been correlated with relevant functional tests for each region of the body analysed. RESULTS: In 181 of the 182 patients scanned, we observed muscle pathology on T1-weighted images, with the gastrocnemius medialis and the soleus being the most commonly affected muscles. A similar pattern of involvement was identified in most patients regardless of their clinical presentation. Increased muscle pathology on MRI correlated positively with disease duration and functional impairment. CONCLUSIONS: The information generated by this study is of high diagnostic value and important for clinical trial development. We have been able to describe a pattern that can be considered as characteristic of dysferlinopathy. We have defined the natural history of the disease from a radiological point of view. These results enabled the identification of the most relevant regions of interest for quantitative MRI in longitudinal studies, such as clinical trials. CLINICAL TRIAL REGISTRATION: NCT01676077.

Impaired Muscle Efficiency but Preserved Peripheral Hemodynamics and Mitochondrial Function With Advancing Age: Evidence From Exercise in the Young, Old, and Oldest-Old.

Muscle weakness in the elderly has been linked to recurrent falls and morbidity; therefore, elucidating the mechanisms contributing to the loss of muscle function and mobility with advancing age is critical. To this aim, we comprehensively examined skeletal muscle metabolic function and hemodynamics in 11 young (23 ± 2 years), 11 old (68 ± 2 years), and 10 oldest-old (84 ± 2 years) physical activity-matched participants. Specifically, oxidative stress markers, mitochondrial function, and the ATP cost of contraction as well as peripheral hemodynamics were assessed during dynamic plantar flexion exercise at 40 per cent of maximal work rate (WRmax). Both the PCr recovery time constant and the peak rate of mitochondrial ATP synthesis were not significantly different between groups. In contrast, the ATP cost of dynamic contractions (young: 1.5 ± 1.0, old: 3.4 ± 2.1, oldest-old: 6.1 ± 3.6 mM min-1 W-1) and systemic markers of oxidative stress were signficantly increased with age, with the ATP cost of contraction being negatively correlated with WRmax (r = .59, p < .05). End-of-exercise blood flow per Watt rose significantly with increasing age (young: 37 ± 20, old: 82 ± 68, oldest-old: 154 ± 93 mL min-1 W-1). These findings suggest that the progressive deterioration of muscle contractile efficiency with advancing age may play an important role in the decline in skeletal muscle functional capacity in the elderly.

Oxygen delivery and the restoration of the muscle energetic balance following exercise: implications for delayed muscle recovery in patients with COPD.

Patients with chronic obstructive pulmonary disease (COPD) experience a delayed recovery from skeletal muscle fatigue following exhaustive exercise that likely contributes to their progressive loss of mobility. As this phenomenon is not well understood, this study sought to examine postexercise peripheral oxygen (O2) transport and muscle metabolism dynamics in patients with COPD, two important determinants of muscle recovery. Twenty-four subjects, 12 nonhypoxemic patients with COPD and 12 healthy subjects with a sedentary lifestyle, performed dynamic plantar flexion exercise at 40% of the maximal work rate (WRmax) with phosphorus magnetic resonance spectroscopy (31P-MRS), near-infrared spectroscopy (NIRS), and vascular Doppler ultrasound assessments. The mean response time of limb blood flow at the offset of exercise was significantly prolonged in patients with COPD (controls: 56 ± 27 s; COPD: 120 ± 87 s; P < 0.05). In contrast, the postexercise time constant for capillary blood flow was not significantly different between groups (controls: 49 ± 23 s; COPD: 51 ± 21 s; P > 0.05). The initial postexercise convective O2 delivery (controls: 0.15 ± 0.06 l/min; COPD: 0.15 ± 0.06 l/min) and the corresponding oxidative adenosine triphosphate (ATP) demand (controls: 14 ± 6 mM/min; COPD: 14 ± 6 mM/min) in the calf were not significantly different between controls and patients with COPD (P > 0.05). The phosphocreatine resynthesis time constant (controls: 46 ± 20 s; COPD: 49 ± 21 s), peak mitochondrial phosphorylation rate, and initial proton efflux were also not significantly different between groups (P > 0.05). Therefore, despite perturbed peripheral hemodynamics, intracellular O2 availability, proton efflux, and aerobic metabolism recovery in the skeletal muscle of nonhypoxemic patients with COPD are preserved following plantar flexion exercise and thus are unlikely to contribute to the delayed recovery from exercise in this population.

Role of MCT1 and CAII in skeletal muscle pH homeostasis, energetics, and function: in vivo insights from MCT1 haploinsufficient mice.

The purpose of this study was to investigate the effects of a partial suppression of monocarboxylate transporter (MCT)-1 on skeletal muscle pH, energetics, and function (MCT1+/- mice). Twenty-four MCT1+/- and 13 wild-type (WT) mice were subjected to a rest-exercise-recovery protocol, allowing assessment of muscle energetics (by magnetic resonance spectroscopy) and function. The study included analysis of enzyme activities and content of protein involved in pH regulation. Skeletal muscle of MCT1+/- mice had lower MCT1 (-61%; P < 0.05) and carbonic anhydrase (CA)-II (-54%; P < 0.05) contents. Although intramuscular pH was higher in MCT1+/- mice at rest (P < 0.001), the mice showed higher acidosis during the first minute of exercise (P < 0.01). Then, the pH time course was similar among groups until exercise completion. MCT1+/- mice had higher specific peak (P < 0.05) and maximum tetanic (P < 0.01) forces and lower fatigability (P < 0.001) when compared to WT mice. We conclude that both MCT1 and CAII are involved in the homeostatic control of pH in skeletal muscle, both at rest and at the onset of exercise. The improved muscle function and resistance to fatigue in MCT1+/- mice remain unexplained.-Chatel, B., Bendahan, D., Hourdé, C., Pellerin, L., Lengacher, S., Magistretti, P., Fur, Y. L., Vilmen, C., Bernard, M., Messonnier, L. A. Role of MCT1 and CAII in skeletal muscle pH homeostasis, energetics, and function: in vivo insights from MCT1 haploinsufficient mice.

Combined quantification of fatty infiltration, T 1-relaxation times and T 2*-relaxation times in normal-appearing skeletal muscle of controls and dystrophic patients.

OBJECTIVES: To evaluate the combination of a fat-water separation method with an automated segmentation algorithm to quantify the intermuscular fatty-infiltrated fraction, the relaxation times, and the microscopic fatty infiltration in the normal-appearing muscle. MATERIALS AND METHODS: MR acquisitions were performed at 1.5T in seven patients with facio-scapulo-humeral dystrophy and eight controls. Disease severity was assessed using commonly used scales for the upper and lower limbs. The fat-water separation method provided proton density fat fraction (PDFF) and relaxation times maps (T 2* and T 1). The segmentation algorithm distinguished adipose tissue and normal-appearing muscle from the T 2* map and combined active contours, a clustering analysis, and a morphological closing process to calculate the index of fatty infiltration (IFI) in the muscle compartment defined as the relative amount of pixels with the ratio between the number of pixels within IMAT and the total number of pixels (IMAT + normal appearing muscle). RESULTS: In patients, relaxation times were longer and a larger fatty infiltration has been quantified in the normal-appearing muscle. T 2* and PDFF distributions were broader. The relaxation times were correlated to the Vignos scale whereas the microscopic fatty infiltration was linked to the Medwin-Gardner-Walton scale. The IFI was linked to a composite clinical severity scale gathering the whole set of scales. CONCLUSION: The MRI indices quantified within the normal-appearing muscle could be considered as potential biomarkers of dystrophies and quantitatively illustrate tissue alterations such as inflammation and fatty infiltration.

Impaired muscle force production and higher fatigability in a mouse model of sickle cell disease.

Skeletal muscle function has been scarcely investigated in sickle cell disease (SCD) so that the corresponding impact of sickle hemoglobin is still a matter of debate. The purpose of this study was to investigate muscle force production and fatigability in SCD and to identify whether exercise intensity could have a modulatory effect. Ten homozygous sickle cell (HbSS), ten control (HbAA) and ten heterozygous (HbAS) mice were submitted to two stimulation protocols (moderate and intense) to assess force production and fatigability. We showed that specific maximal tetanic force was lower in HbSS mice as compared to other groups. At the onset of the stimulation period, peak force was reduced in HbSS and HbAS mice as compared to HbAA mice. Contrary to the moderate protocol, the intense stimulation protocol was associated with a larger decrease in peak force and rate of force development in HbSS mice as compared to HbAA and HbAS mice. These findings provide in vivo evidence of impaired muscle force production and resistance to fatigue in SCD. These changes are independent of muscle mass. Moreover, SCD is associated with muscle fatigability when exercise intensity is high.

Evidence of a metabolic reserve in the skeletal muscle of elderly people.

The purpose of the present study was to determine whether mitochondrial function is limited by O2 availability or the intrinsic capacity of mitochondria to synthesize ATP in elderly individuals. To this aim, we examined, in comparison to free-flow conditions (FF), the effect of superimposing reactive hyperemia (RH), induced by a period of brief ischemia during the last min of exercise, on O2 availability and mitochondrial function in the calf muscle. 12 healthy, untrained, elderly subjects performed dynamic plantar flexion exercise and phosphorus magnetic resonance spectroscopy (31P-MRS), near-infrared spectroscopy (NIRS), and Doppler ultrasound were used to assess muscle metabolism and peripheral hemodynamics. Limb blood flow [area under the curve (AUC), FF: 1.5±0.5L; RH: 3.2±1.1L, P<0.01] and convective O2 delivery (AUC, FF: 0.30±0.13L; RH: 0.64±0.29L, P<0.01) were significantly increased in RH in comparison to FF. RH was also associated with significantly higher capillary blood flow (P<0.05) and this resulted in a 33% increase in estimated peak mitochondrial ATP synthesis rate (FF: 24±11 mM.min-1; RH: 31±7 mM.min-1, P<0.05). These results document a hemodynamic reserve in the contracting calf muscle of the elderly accessible by superimposing reactive hyperemia. Furthermore, this increase in O2 availability enhanced mitochondrial function thus indicating a skeletal muscle metabolic reserve despite advancing age and low level of physical activity.

Creatine, Glutamine plus Glutamate, and Macromolecules Are Decreased in the Central White Matter of Premature Neonates around Term.

Preterm birth represents a high risk of neurodevelopmental disabilities when associated with white-matter damage. Recent studies have reported cognitive deficits in children born preterm without brain injury on MRI at term-equivalent age. Understanding the microstructural and metabolic underpinnings of these deficits is essential for their early detection. Here, we used diffusion-weighted imaging and single-voxel 1H magnetic resonance spectroscopy (MRS) to compare brain maturation at term-equivalent age in premature neonates with no evidence of white matter injury on conventional MRI except diffuse excessive high-signal intensity, and normal term neonates. Thirty-two infants, 16 term neonates (mean post-conceptional age at scan: 39.8±1 weeks) and 16 premature neonates (mean gestational age at birth: 29.1±2 weeks, mean post-conceptional age at scan: 39.2±1 weeks) were investigated. The MRI/MRS protocol performed at 1.5T involved diffusion-weighted MRI and localized 1H-MRS with the Point RESolved Spectroscopy (PRESS) sequence. Preterm neonates showed significantly higher ADC values in the temporal white matter (P<0.05), the occipital white matter (P<0.005) and the thalamus (P<0.05). The proton spectrum of the centrum semiovale was characterized by significantly lower taurine/H2O and macromolecules/H2O ratios (P<0.05) at a TE of 30 ms, and reduced (creatine+phosphocreatine)/H2O and (glutamine+glutamate)/H2O ratios (P<0.05) at a TE of 135 ms in the preterm neonates than in full-term neonates. Our findings indicate that premature neonates with normal conventional MRI present a delay in brain maturation affecting the white matter and the thalamus. Their brain metabolic profile is characterized by lower levels of creatine, glutamine plus glutamate, and macromolecules in the centrum semiovale, a finding suggesting altered energy metabolism and protein synthesis.