Moderate and intense muscular exercises induce marked intramyocellular metabolic acidosis in sickle cell disease mice

Abstract

Sickle cell disease (SCD) is associated with an impaired oxygen delivery to skeletal muscle that could alter ATP production processes. The present study aimed to determine the effects of sickle hemoglobin (HbS) on muscle pH homeostasis in response to exercise in homozygous (HbSS, = 9) and heterozygous (HbAS, = 10) SCD (Townes) mice in comparison to control (HbAA, = 10) littermates. Magnetic resonance spectroscopy of phosphorus 31 enabled to measure intramuscular pH and phosphocreatine (PCr) concentration during rest-stimulation-recovery protocols at two different intensities. Maximal activity of some enzymes involved in muscle energetics and content of proteins involved in pH regulation were also investigated. HbSS mice presented a more pronounced exercise-induced intramuscular acidosis, whatever the intensity of exercise. Moreover, the depletion of PCr was also exacerbated in HbSS mice in response to intense exercise as compared with both HbAA and HbAS mice ( < 0.01). While no difference was observed concerning proteins involved in muscle pH regulation, the activity of enolase (a glycolytic enzyme) was higher in both HbSS and HbAS mice as compared with controls ( < 0.05). Interestingly, HbAS mice presented also metabolic impairments as compared with their control counterparts. This study has identified for the first time an exacerbated exercise-induced intramuscular acidosis in SCD mice. The main finding of the present study was that the exercise-induced intramuscular acidosis was systematically more pronounced in sickle cell disease (SCD) mice as compared with their control counterparts. This result is important since it has been demonstrated in vitro that acidosis can trigger hemoglobin polymerization. From that point of view, our results tend to support the idea that high-intensity exercise may increase the risk of hemoglobin polymerization in SCD.

Exacerbated in vivo metabolic changes suggestive of a spontaneous muscular vaso-occlusive crisis in exercising muscle of a sickle cell mouse

“…We used magnetic resonance spectroscopy of phosphorus 31 ( 31 P-MRS) in order to assess changes in phosphocreatine (PCr) and inorganic phosphate (P i ) concentrations as well as intramuscular pH throughout two different exercise protocols. In this study, we have reported a more pronounced intramuscular exercise-induced acidosis in SCD mice as compared to their control counterparts [7]. During these investigations, one mouse displayed drastically divergent deviations from the metabolic profile we recorded for the other SCD mice during the moderate intensity protocol.…”

“…In a previous study aiming at evaluating the impacts of HbS on skeletal muscle metabolism [7], we submitted control and SCD mice to standardized rest -stimulationrecovery protocols. We used magnetic resonance spectroscopy of phosphorus 31 ( 31 P-MRS) in order to assess changes in phosphocreatine (PCr) and inorganic phosphate (P i ) concentrations as well as intramuscular pH throughout two different exercise protocols.…”

“…Anesthetized animal were placed supine within a home-built cradle especially designed for a strictly non-invasive investigation of posterior hindlimb muscle energetics during electrical stimulation [7]. Investigations were performed using a 47/30 Biospec Avance MR system (Bruker, Karlsruhe, Germany) equipped with a 120-mm BGA12SL (200 mT/m) gradient insert.…”

“…If this type of crisis has been acknowledged in many tissues [2], the potential occurrence of such an event in skeletal muscle has rarely been documented [3; 4; 5; 6]. To the best of our knowledge, no direct observation of a skeletal muscle VOC has been performed in real time.In a previous study aiming at evaluating the impacts of HbS on skeletal muscle metabolism [7], we submitted control and SCD mice to standardized rest -stimulationrecovery protocols. We used magnetic resonance spectroscopy of phosphorus 31 ( 31 P-MRS) in order to assess changes in phosphocreatine (PCr) and inorganic phosphate (P i ) concentrations as well as intramuscular pH throughout two different exercise protocols.…”

“…MIE (moderate intensity exercise) and HIE (high-intensity exercise), performed 48 hours apart in a random order. The animal suspected to develop a VOC (called M1) initially performed the HIE and then the MIE.Anesthetized animal were placed supine within a home-built cradle especially designed for a strictly non-invasive investigation of posterior hindlimb muscle energetics during electrical stimulation [7]. Investigations were performed using a 47/30 Biospec Avance MR system (Bruker, Karlsruhe, Germany) equipped with a 120-mm BGA12SL (200 mT/m) gradient insert.…”