Three‐dimensional mapping of the creatine kinase enzyme reaction rate in muscles of the lower leg

Abstract

Phosphorous (31P) magnetization transfer (MT) techniques enable the non-invasive measurement of metabolic turnover rates of important enzyme catalyzed reactions, such as the creatine kinase reaction (CK), a major transducing reaction involving adenosine triphosphate and phosphocreatine. Alteration in the kinetics of the CK reaction rate appears to play a central role in many disease states. In this study, we developed and implemented at ultra-high field (7T), a novel three-dimensional 31P-MT imaging sequence that maps the kinetics of CK in the entire volume of the lower leg at relatively high resolution (0.52 mL voxel size), and within acquisition times that can be tolerated by patients (below 60 min). We tested the sequence on five healthy and two clinically diagnosed type 2-diabetic patients. Overall, we obtained measurements that are in close agreement with measurements reported previously using spectroscopic methods. Importantly, our spatially resolved method allowed us to measure local CK reaction rate constants and metabolic fluxes in individual muscles in healthy subjects. Furthermore, in the case of patients with diabetes, it allowed us to detect variations of the CK rate of different muscles, which would not have been possible using unlocalized MRS methods. The results of this work suggest that 3D-mapping of the CK reaction rates and metabolic fluxes can be achieved in the skeletal muscle in vivo at relatively high spatial resolution and with acquisition times well tolerated by patients. The ability to measure bioenergetics simultaneously in large areas of muscles will bring new insights into possible heterogeneous patterns of muscle metabolism associated with several diseases and serve as a valuable tool for monitoring the efficacy of interventions.

Feasibility and repeatability of localized 31P‐MRS four‐angle saturation transfer (FAST) of the human gastrocnemius muscle using a surface coil at 7 T

“…Our data show that the measurements with the DRESS‐localized FAST method in the gastrocnemius muscle are feasible at 7 T, even without the use of adiabatic excitation pulses. The measured k values for PCr‐to‐ATP ( k CK = 0.26 ± 0.05 s −1 ) and P i ‐to‐ATP ( k ATP = 0.11 ± 0.05 s −1 ) reactions are in good agreement with previously published results of localized experiments . Bottomley et al reported a k CK for localized FAST of 0.29 ± 0.07 s −1 .…”

“…In their study, the localization was achieved by adding a 1D phase‐encoding gradient pulse after the excitation BIR4 pulse, and localized FAST data were acquired in 17–39 min (PCr‐to‐ATP exchange only) at 1.5 T . In a 3D‐TSE (turbo spin echo) imaging study of calf muscles at 7 T, Parasoglou et al used continuous ST and IR to measure the PCr‐to‐ATP exchange rates of the gastrocnemius muscle (0.31 ± 0.05 s −1 ) in 60 min . The P i ‐to‐ATP chemical exchange rate constant measured in the gastrocnemius muscle by Parasoglou et al in a different 31 P‐MR imaging experiment at 7 T was 0.11 ± 0.04 s −1 .…”

Creatine kinase rate constant in the human heart measured with 3D‐localization at 7 tesla

“…These simulations are corroborated by the results in skeletal muscle. For both 3T and 7T experiments, the average agrees with the literature measurements that span 0.23 s −1 to 0.35 s −?1 (or 0.459 s −1 if inversion transfer is included ). At 3T, despite the low variation in flip angle, the SNR is relatively low compared to 7T and a correspondingly high estimated CRLB, and high intervoxel variance of is observed.…”

Assessing tissue metabolism by phosphorous-31 magnetic resonance spectroscopy and imaging: a methodology review

“…Since changes in PCr and P i during a perturbation protocol are closely associated with mitochondrial function, these two metabolites are frequently the focus of spectrally selective 31 P imaging studies. To select the metabolite of interest (e.g., PCr) for imaging, a frequency-selective excitation pulse can be used without the presence of a slice-selective gradient (147,148). The subsequent image acquisition using phaseand frequency-encoding gradients is similar to that of 1 H…”

“…An interleaved excitation scheme further enables simultaneous quantification of PCr and P i , which allows the quantification of pH from the phase difference between PCr and P i (156). Furthermore, MT has also been incorporated into this approach to allow the mapping of the CK reaction rate (147,148). Comparing to conventional MRSI methods, imaging techniques using spectrally selective approaches provide the opportunity for improved spatial resolution with reduced imaging time, which enables dynamic metabolic mapping during a perturbation protocol.…”