Method for Controlled Mitochondrial Perturbation during Phosphorus MRS in Children

Abstract

Introduction Insulin resistance (IR) is increasingly prevalent in children, and may be related to muscle mitochondrial dysfunction, necessitating development of mitochondrial assessment techniques. Recent studies used 31Phosphorus magnetic resonance spectroscopy (31P-MRS), a non-invasive technique appealing for clinical research. 31P-MRS requires exercise at a precise percentage of maximum volitional contraction (MVC). MVC measurement in children, particularly with disease, is problematic due to variability in perception of effort and motivation. We therefore developed a method to predict MVC, using maximal calf muscle cross-sectional area (MCSA) to assure controlled and reproducible muscle metabolic perturbations. Methods Data were collected from 66 sedentary 12–20 year-olds. Plantar flexion-volitional MVC was assessed using a MRI-compatible exercise treadle device. MCSA of the calf muscles were measured from MRI images. Data from the first 26 participants were utilized to model the relationship between MVC and MCSA (predicted MVC = 24.763+0.0047*MCSA). This model was then applied to the subsequent 40 participants. Results Volitional vs. model-predicted mean MVC was 43.9±0.8 kg vs. 44.2±1.81 (P=0.90). 31P-MRS results when predicted and volitional MVC were similar showed expected changes during volitional MVC-based exercise. In contrast, volitional MVC was markedly lower than predicted in 4 participants, and produced minimal metabolic perturbation. Upon repeat testing, these individuals could perform their predicted MVC with coaching, which produced expected metabolic perturbations. Conclusions Compared to using MVC testing alone, utilizing MRI to predict muscle strength allows for a more accurate and standardized 31P-MRS protocol during exercise in children. This method overcomes a major obstacle in assessing mitochondrial function in youth. These studies have importance as we seek to determine the role of mitochondrial function in youth with IR and diabetes and response to interventions.

Muscle oxidative phosphorylation quantitation using creatine chemical exchange saturation transfer (CrCEST) MRI in mitochondrial disorders

“…However, to address this potential source of variance in τCr measurements, percentage CrCEST was included in statistical models as a covariate. Additional studies would be further strengthened by setting exercise parameters in accordance with individual work capacity, and including the work performed by each subject as a covariate (33,34). In addition, it will be useful to validate techniques for individualizing exercise intensity so as to standardize percentage change in CrCEST across participants of different abilities and levels of fitness when τCr is prioritized as the main outcome.…”

Insulin resistance in type 2 diabetes youth relates to serum free fatty acids and muscle mitochondrial dysfunction

“…Imaging and spectroscopy were performed on a General Electric (GE) 3 T magnet with HDx MRI (GE, Milwaukee, WI) running Version 15M4 software equipped with the GE multi-nuclear spectroscopy accessory of hardware and research software and a custom 1 H/ 31 P leg coil (Clinical MR Solutions, Brookfield, WI) (Cree-Green et al, 2014). The coil is a concentric probe made of an inner coil 9 cm in diameter (for 31 P) and a 13 cm outer coil tuned to 1 H frequency for scout imaging and shimming.…”

“…The coil is a concentric probe made of an inner coil 9 cm in diameter (for 31 P) and a 13 cm outer coil tuned to 1 H frequency for scout imaging and shimming. Cross-sectional area for the calf was measured as previously described (Cree-Green et al, 2014). …”

“…Strength testing to determine maximal volitional contraction (MVC) was done on a custom-built MR-compatible plantar flexion device with force measurement capability and force during the exercise perturbation recorded as previously described (Cree-Green et al, 2014; Larson-Meyer, Newcomer, Hunter, Hetherington, & Weinsier, 2000). …”

Peripheral insulin resistance in obese girls with hyperandrogenism is related to oxidative phosphorylation and elevated serum free fatty acids

“…31 P MRS exercise protocol. Strength testing was done on a custombuilt MR-compatible plantar flexion device with force measurement capability as previously described (3,9,31,48). The force transducer box was connected to an external read-out stage (Omega Engineering, Stamford, CT), and finally to a laptop computer for constant recording of force throughout exercise with DAQ software (Labview, National Instruments, Austin, TX).…”