Metabolic underpinnings of the paradoxical net phosphocreatine resynthesis in contracting rat gastrocnemius muscle

AbstractNet phosphocreatine (PCr) resynthesis during muscle contraction is a paradoxical phenomenon because it occurs under conditions of high energy demand. The metabolic underpinnings of this phenomenon were analyzed non-invasively using 31P-magnetic resonance spectroscopy in rat gastrocnemius muscle (n=11) electrically stimulated (7.6 Hz, 6 min duration) in situ under ischemic and normoxic conditions. During ischemic stimulation, [PCr] initially fell to a steady state (9±5% of resting concentration) which was maintained for the last 5 min of stimulation, whereas isometric force production decreased to a non-measurable level beyond 3 min. Throughout normoxic stimulation, [PCr] and force production declined to a steady state after respectively 1 min (5±3% of resting concentration) and 3.25 min (21±8% of initial value) of stimulation. Contrary to the observations under ischemia, a paradoxical net PCr resynthesis was recorded during the last 2 min of normoxic stimulation and was not accompanied by any improvement in force production. These results demonstrate that the paradoxical net PCr resynthesis recorded in contracting muscle relies exclusively on oxidative energy production and could occur in inactivated fibers, similarly to PCr resynthesis during post-exercise recovery

Effect of citrulline malate supplementation on muscle function and bioenergetics during short-term repeated bouts of fatiguing exercise

International audienceCitrulline malate (CM) has been shown to improve muscle performance in healthy participants during a single exercise session. Yet, within the framework of exercises repeated at close time interval, the consequences of CM ingestion on mechanical performance are controversial and the bioenergetics side remains undocumented. The aim of this double-blind placebo-controlled study was to evaluate in vivo the effect of short-term (7 doses in 48h) oral administration of CM upon gastrocnemius muscle function and bioenergetics using noninvasive multimodal NMR techniques in healthy rats. The experimental protocol consisted of two 6-min bouts of fatiguing exercise spaced by an 8-min recovery period. CM treatment did not affect the basal bioenergetics status and increased the half-fatigue time during the first exercise bout. With exercise repetition, it prevented PCr cost alteration and decreased both the glycolytic ATP production and the contractile ATP cost in working muscle, but these changes were not associated to any improvement in mechanical performance. Besides, CM did not influence the replenishment of high-energy phosphorylated compounds during the post-exercise recovery periods. Therefore, short-term CM administration enhances muscle bioenergetics throughout fatiguing bouts of exercise repeated at close time interval but this enhancement does not benefit to mechanical performance

Effect of citrulline malate supplementation on muscle function and bioenergetics during short-term repeated bouts of fatiguing exercise

International audienceCitrulline malate (CM) has been shown to improve muscle performance in healthy participants during a single exercise session. Yet, within the framework of exercises repeated at close time interval, the consequences of CM ingestion on mechanical performance are controversial and the bioenergetics side remains undocumented. The aim of this double-blind placebo-controlled study was to evaluate in vivo the effect of short-term (7 doses in 48h) oral administration of CM upon gastrocnemius muscle function and bioenergetics using noninvasive multimodal NMR techniques in healthy rats. The experimental protocol consisted of two 6-min bouts of fatiguing exercise spaced by an 8-min recovery period. CM treatment did not affect the basal bioenergetics status and increased the half-fatigue time during the first exercise bout. With exercise repetition, it prevented PCr cost alteration and decreased both the glycolytic ATP production and the contractile ATP cost in working muscle, but these changes were not associated to any improvement in mechanical performance. Besides, CM did not influence the replenishment of high-energy phosphorylated compounds during the post-exercise recovery periods. Therefore, short-term CM administration enhances muscle bioenergetics throughout fatiguing bouts of exercise repeated at close time interval but this enhancement does not benefit to mechanical performance

Comparative MRI analysis of T2 changes associated with single and repeated bouts of downhill running leading to eccentric-induced muscle damage.

Although the exact mechanisms are still unclear, it is commonly acknowledged that acute eccentric exercise alters muscle performance whereas the repetition of successive bouts leads to the disappearance of the deleterious signs. In order to clarify this issue, we measured blood creatine kinase, lactate dehydrogenase activities and proton T2 relaxation time in various leg muscles 72 hours after a single and repeated bouts of exhausting downhill running sessions (-15 degrees ;1.5km/h), elapsed by either 4 or 7-days. After a single exercise bout, T2 and enzyme activities initially increased and recovered rapidly. When exercise bouts were repeated over a short time period (4-days), initial changes did not recover and endurance time throughout additional exercise sessions was significantly reduced. On the contrary, with a longer resting time between exercises (7-days), endurance time of additional running sessions was significantly longer and muscle changes (T2 increase, muscle oedema and enzyme activities changes) slowly and completely reversed. Significant correlations were found between T2 changes and enzymes activities. T2 changes in the soleus and gastrocnemius muscle heads were differently affected by lengthening contractions suggesting a muscle-specificity and indicating that muscle alterations might be linked to different anatomical properties such as fiber pennation angles, typology and/or to the exhausting nature of the downhill running sessions. We documented a "less muscle injury" effect due to the repetition of exercise bouts at a low frequency (i.e. 1 session per week), in accordance with the delayed muscle inflammation. This effect was not observed when the between-exercise resting time was shorter. Key words: eccentric, skeletal muscle, rat, lengthening, functional MR imaging

Effect of citrulline malate supplementation on muscle function and bioenergetics during short-term repeated bouts of fatiguing exercise

International audienceCitrulline malate (CM) has been shown to improve muscle performance in healthy participants during a single exercise session. Yet, within the framework of exercises repeated at close time interval, the consequences of CM ingestion on mechanical performance are controversial and the bioenergetics side remains undocumented. The aim of this double-blind placebo-controlled study was to evaluate in vivo the effect of short-term (7 doses in 48h) oral administration of CM upon gastrocnemius muscle function and bioenergetics using noninvasive multimodal NMR techniques in healthy rats. The experimental protocol consisted of two 6-min bouts of fatiguing exercise spaced by an 8-min recovery period. CM treatment did not affect the basal bioenergetics status and increased the half-fatigue time during the first exercise bout. With exercise repetition, it prevented PCr cost alteration and decreased both the glycolytic ATP production and the contractile ATP cost in working muscle, but these changes were not associated to any improvement in mechanical performance. Besides, CM did not influence the replenishment of high-energy phosphorylated compounds during the post-exercise recovery periods. Therefore, short-term CM administration enhances muscle bioenergetics throughout fatiguing bouts of exercise repeated at close time interval but this enhancement does not benefit to mechanical performance

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

International audienceOur 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 SCD 4 m-HU mice displayed a higher specific force production as compared with SCD 4 m mice. In that respect, HU treatment would help to maintain a higher capacity of force production during aging in SCD

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

International audienceSickle 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

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

International audienceHydroxyurea (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 31 Phosphorus 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/mm 3 and 437.43 ± 57.10 N/mm 3 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

Mitochondrial impairment induced by postnatal ActRIIB blockade does not alter function and energy status in exercising mouse glycolytic muscle in vivo

International audienceBecause it leads to a rapid and massive muscle hypertrophy, postnatal blockade of the activin type IIB receptor (ActRIIB) is a promising therapeutic strategy for counteracting muscle wasting. However, the functional consequences remain very poorly documented in vivo. Here, we have investigated the impact of 8-wk ActRIIB blockade with soluble receptor (sActRIIB-Fc) on gastrocnemius muscle anatomy, energy metabolism, and force-generating capacity in wild-type mice, using totally noninvasive magnetic resonance imaging (MRI) and dynamic 31 P-MRS. Compared with vehicle (PBS) control, sActRIIB-Fc treatment resulted in a dramatic increase in body weight (+29%) and muscle volume (+58%) calculated from hindlimb MR imaging, but did not alter fiber type distribution determined via myosin heavy chain isoform analysis. In resting muscle, sActRIIB-Fc treatment induced acidosis and PCr depletion, thereby suggesting reduced tissue oxygenation. During an in vivo fatiguing exercise (6-min repeated maximal isometric contraction electrically induced at 1.7 Hz), maximal and total absolute forces were larger in sActRIIB-Fc treated animals (+26 and +12%, respectively), whereas specific force and fatigue resistance were lower (−30 and −37%, respectively). Treatment with sActRIIB-Fc further decreased the maximal rate of oxidative ATP synthesis (−42%) and the oxidative capacity (−34%), but did not alter the bioenergetics status in contracting muscle. Our findings demonstrate in vivo that sActRIIB-Fc treatment increases absolute force-generating capacity and reduces mitochondrial function in glycolytic gastrocnemius muscle, but this reduction does not compromise energy status during sustained activity. Overall, these data support the clinical interest of postnatal ActRIIB blockade

Deletion of the microtubule-associated protein 6 (MAP6) results in skeletal muscle dysfunction

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