Muscle oxidative phosphorylation quantitation using creatine chemical exchange saturation transfer (CrCEST) MRI in mitochondrial disorders
Catherine DeBrosse, Ravi Prakash Reddy Nanga, Neil Wilson, Kevin D’Aquilla, Mark Elliott, Hari Hariharan, Felicia Yan, Kristin Wade, Sara Nguyen, Diana Worsley, Chevonne Parris-Skeete, Elizabeth McCormick, Rui Xiao, Zuela Zolkipli Cunningham, Lauren Fishbein, Katherine L. Nathanson, David R. Lynch, Virginia A. Stallings, Marc Yudkoff, Marni J. Falk, Ravinder Reddy, Shana E. McCormack
Catherine DeBrosse, Ravi Prakash Reddy Nanga, Neil Wilson, Kevin D’Aquilla, Mark Elliott, Hari Hariharan, Felicia Yan, Kristin Wade, Sara Nguyen, Diana Worsley, Chevonne Parris-Skeete, Elizabeth McCormick, Rui Xiao, Zuela Zolkipli Cunningham, Lauren Fishbein, Katherine L. Nathanson, David R. Lynch, Virginia A. Stallings, Marc Yudkoff, Marni J. Falk, Ravinder Reddy, Shana E. McCormack
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Resource and Technical Advance Metabolism

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

Abstract

Systemic mitochondrial energy deficiency is implicated in the pathophysiology of many age-related human diseases. Currently available tools to estimate mitochondrial oxidative phosphorylation (OXPHOS) capacity in skeletal muscle in vivo lack high anatomic resolution. Muscle groups vary with respect to their contractile and metabolic properties. Therefore, muscle group–specific estimates of OXPHOS would be advantageous. To address this need, a noninvasive creatine chemical exchange saturation transfer (CrCEST) MRI technique has recently been developed, which provides a measure of free creatine. After exercise, skeletal muscle can be imaged with CrCEST in order to make muscle group–specific measurements of OXPHOS capacity, reflected in the recovery rate (τCr) of free Cr. In this study, we found that individuals with genetic mitochondrial diseases had significantly (P = 0.026) prolonged postexercise τCr in the medial gastrocnemius muscle, suggestive of less OXPHOS capacity. Additionally, we observed that lower resting CrCEST was associated with prolonged τPCr, with a Pearson’s correlation coefficient of –0.42 (P = 0.046), consistent with previous hypotheses predicting that resting creatine levels may correlate with 31P magnetic resonance spectroscopy–based estimates of OXPHOS capacity. We conclude that CrCEST can noninvasively detect changes in muscle creatine content and OXPHOS capacity, with high anatomic resolution, in individuals with mitochondrial disorders.

Authors

Catherine DeBrosse, Ravi Prakash Reddy Nanga, Neil Wilson, Kevin D’Aquilla, Mark Elliott, Hari Hariharan, Felicia Yan, Kristin Wade, Sara Nguyen, Diana Worsley, Chevonne Parris-Skeete, Elizabeth McCormick, Rui Xiao, Zuela Zolkipli Cunningham, Lauren Fishbein, Katherine L. Nathanson, David R. Lynch, Virginia A. Stallings, Marc Yudkoff, Marni J. Falk, Ravinder Reddy, Shana E. McCormack

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Figure 1

Example resting and postexercise CrCEST recovery images and summary curves.

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Example resting and postexercise CrCEST recovery images and summary curv...
(A–D) (left) Images from a heathy 21-year-old female. (E–H) (right) Images from a 21-year-old female with a mitochondrial DNA mutation, m.1630G>A (tRNA-Val) with hearing impairment, short stature, and stroke (53). Panels A and E show the sequential resting creatine chemical exchange saturation transfer (CrCEST) images (1 image every 30 seconds at rest), overlaid on the manually segmented, anatomical axial calf muscle image, for the healthy and affected individuals, respectively. The images encompass the muscle region of the right calf. The intensity of the color in each image, as shown on the color bar, is in proportion to the CrCEST percentage asymmetry signal, reflecting the amount of free creatine. Resting CrCEST appears lower in the affected individual as well (e.g., in soleus, CrCEST asymmetry is 11.1% in the affected individual versus 13.2% in healthy individual). Panels B and F show the sequential postexercise images (1 image every 30 seconds after cessation of exercise) in the healthy and affected individuals, respectively. Both subjects exercised, as indicated by the increase in free creatine, although the specific muscle groups used differ, and the percentage change in CrCEST for the same exercise was higher in the affected individual (e.g., in the soleus, 28% in the affected individual versus 10% in the healthy control). By ~2 minutes after exercise, the healthy volunteer’s CrCEST image resembles the baseline image, but in the affected individual, the exponential time constant for the decline in Cr after exercise (τCr) is prolonged (e.g., in the soleus, 5.9 minutes in the affected individual versus 1.1 minutes in the healthy control). Panels C and G show the postexercise CrCEST signal recovery summarized over the anatomic region corresponding to the approximate area of the surface 31P-MRS coil. Panels D and H show the postexercise phosphocreatine (PCr) signal recovery in this same anatomic region. In both modalities, prolonged postexercise recovery is observed in the affected individual relative to the healthy individual.