Muscle oxidative phosphorylation quantitation using creatine chemical exchange saturation transfer (CrCEST) MRI in mitochondrial disorders.
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 with31P 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.
Center for Magnetic Resonance and Optical Imaging, Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Catherine
C
DeBrosse
Center for Magnetic Resonance and Optical Imaging, Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Ravi Prakash Reddy
RPR
Nanga
Center for Magnetic Resonance and Optical Imaging, Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Neil
N
Wilson
Center for Magnetic Resonance and Optical Imaging, Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Kevin
K
D'Aquilla
Center for Magnetic Resonance and Optical Imaging, Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Mark
M
Elliott
Center for Magnetic Resonance and Optical Imaging, Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Hari
H
Hariharan
Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia.
Felicia
F
Yan
Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia.
Kristin
K
Wade
Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia.
Sara
S
Nguyen
Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia.
Diana
D
Worsley
Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia.
Chevonne
C
Parris-Skeete
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Elizabeth
E
McCormick
Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Rui
R
Xiao
Department of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Zuela Zolkipli
ZZ
Cunningham
Division of Endocrinology, Metabolism, and Diabetes, University of Colorado School of Medicine, Aurora, Colorado, USA.
Lauren
L
Fishbein
Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania.|Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania.
Katherine L
KL
Nathanson
Department of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
David R
DR
Lynch
Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia.|Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Virginia A
VA
Stallings
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.|Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Marc
M
Yudkoff
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.|Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Marni J
MJ
Falk
Center for Magnetic Resonance and Optical Imaging, Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Ravinder
R
Reddy
Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia.|Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Shana E
SE
McCormack
D000328:Adult; D003401:Creatine / Q000737:chemistry*; D005080:Exercise Test; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D008931:Mitochondria, Muscle; D028361:Mitochondrial Diseases / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D010725:Phosphocreatine; D010766:Phosphorylation
D010725:Phosphocreatine; D003401:Creatine