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 4

Correlogram of the association between intentional exercise, expressed either as hours per week (reflecting time spent exercising), or MET per week (reflecting both time and intensity spent exercising) and measured imaging parameters.

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Correlogram of the association between intentional exercise, expressed e...
The results of nonparametric correlation analyses are shown for all participants (first group of 2 columns), for participants with mitochondrial disease (second group of 2 columns), and for control participants (third group of 2 columns). Groups are separated by horizontal black lines. The bottom 4 rows indicate baseline (i.e., preexercise) metabolite concentration: baseline creatine chemical exchange saturation transfer (CrCEST) in the soleus, medial gastrocnemius, and lateral gastrocnemius, and phosphocreatine to inorganic phosphate ratio (PCr/Pi) in the region of interest captured by 31P magnetic resonance spectroscopy (31P-MRS). A higher resting CrCEST or PCr/Pi value suggests more bioenergetic capacity at rest. The top 4 rows indicate postexercise exponential time constants for return to baseline of CrCEST in soleus, medial gastrocnemius, and lateral gastrocnemius, and PCr in the region of interest captured by 31P-MRS. A longer postexercise time constant to return to baseline suggests decreased oxidative phosphorylation capacity. The 2 types of imaging assessment (baseline, postexercise) are separated by the dashed horizontal black line. As indicated by the color bar, positive associations are shown in red, and negative associations in yellow. *Nominal P value < 0.05; **Bonferroni P value < 0.05 (adjusted for the 16 comparisons shown for each group). BL, baseline; Sol, soleus; MG, medial gastrocnemius; Mito, mitochondrial; LG, lateral gastrocnemius.