Prediction of Muscle Energy States at Low Metabolic Rates Requires Feedback Control of Mitochondrial Respiratory Chain Activity by Inorganic Phosphate

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 31P nuclear magnetic resonance spectroscopy (31P 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 (ΔGp = ΔGpo′+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 31P 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

Elevated risk of infection with SARS-CoV-2 Beta, Gamma, and Delta variants compared with Alpha variant in vaccinated individuals

The extent to which severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) break through infection- or vaccine-induced immunity is not well understood. We analyzed 28,578 sequenced SARS-CoV-2 samples from individuals with known immune status obtained through national community testing in the Netherlands from March to August 2021. We found evidence of an increased risk of infection by the Beta (B.1.351), Gamma (P.1), or Delta (B.1.617.2) variants compared with the Alpha (B.1.1.7) variant after vaccination. No clear differences were found between vaccines. However, the effect was larger in the first 14 to 59 days after complete vaccination compared with ≥60 days. In contrast to vaccine-induced immunity, there was no increased risk for reinfection with Beta, Gamma, or Delta variants relative to the Alpha variant in individuals with infection-induced immunity.</p

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

Rationale and Objectives: The clinical utility of supine in-magnet bicycling in combination with phosphorus magnetic resonance spectroscopy (P-31 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 P-31 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 P-31 MRS to assess and monitor muscle energetic patterns in pediatric patients with inflammatory myopathies

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

Rationale and Objectives: The clinical utility of supine in-magnet bicycling in combination with phosphorus magnetic resonance spectroscopy (31P 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 31P 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 31P MRS to assess and monitor muscle energetic patterns in pediatric patients with inflammatory myopathies

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

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

MRI image with CSI dataset.

<p>T₁ weighted gradient echo image with the measured 2D CSI dataset. The selected voxel in the vastus lateralis muscle with the related ³¹P spectrum is shown in yellow.</p

³¹P spectra from a trained and an untrained subject.

<p>³¹P spectra from a trained and an untrained subject, after a 3 Hz Lorentzian window function was applied. The Pi₂ intensity is higher in the trained subject. Spectra are scaled to the PCr resonance peak. Peaks visible: two signals for inorganic phosphate (Pi₁ and Pi₂), glycerol phosphocholine (GPC), glycerol phosphoethanolamine (GPE), phosphocreatine(PCr), γ-adenosine triphosphate (γ-ATP). The inset shown the two signals for inorganic phosphate (Pi₁ and Pi₂) in the trained and untrained subjects in more detail.</p

Bar plot Pi₂/Pi₁ ratio trained/untrained.

<p>Bar plot of Pi₂/Pi₁ ratio with a significant higher Pi₂/Pi₁ in the endurance trained athletes (0.07 ± 0.01) compared to the normal physical active group (0.03 ± 0.01) (P < 0.05).</p

Bar plot of PCr recovery rate trained/untrained.

<p>Bar plot of PCr recovery rate with a significant faster τ_PCr in the endurance trained athletes (12 ± 3 s) compared to the normal physical active group (24 ± 5 s) (P < 0.05).</p

Model prediction of the relation between PCr recovery time constant and Pi₂/Pi₁.

<p>Model prediction of the relation between PCr recovery time constant and Pi₂/Pi₁. Experimental data points from the trained group are indicated by o, and from the untrained group with *.</p