Project Grant R01HL170039

DEVELOPMENT OF EARLY METABOLIC IMAGING BIOMARKERS FOR MUSCULAR DYSTROPHY AND CARDIOMYOPATHY IN PATIENTS - PROJECT SUMMARY/ABSTRACT DYSTROPHINOPATHY IS A GROUP OF X-LINKED NEUROMUSCULAR DISORDERS, RESULTING FROM MUTATIONS IN THE DYSTROPHIN GENES. DUCHENNE MUSCULAR DYSTROPHY (DMD) AND A MILDER FORM, BECKER MUSCULAR DYSTROPHY (BMD), ARE THE MOST COMMON FORMS OF DYSTROPHINOPATHY. BOTH TYPES OF MUSCULAR DYSTROPHY (MD) PATIENTS DEVELOP PROGRESSIVE WASTING OF SKELETAL MUSCLE AND HEART FAILURE, AND CURRENTLY THERE IS NO ABSOLUTE CURE. DESPITE EXTENSIVE INVESTIGATION INTO THE MANAGEMENT OF MD, TOOLS FOR MONITORING THE DISEASE PROGRESSION AND THE TREATMENT RESPONSE ARE YET TO BE ESTABLISHED. MITOCHONDRIAL DYSFUNCTION AND INFLAMMATION ARE INDICATIVE METABOLIC PHENOTYPES OF THE SEVERITY OF DYSTROPHINOPATHY AND PRECEDE MUSCLE DAMAGE, PLAYING CAUSATIVE ROLES IN THE PATHOGENESIS OF MD. PATIENTS WITH MD HAVE DECREASED LEVEL OF GLUCOSE IN THE SKELETAL MUSCLE AND THE MYOCARDIUM, CONTRIBUTING TO THE LOW CONCENTRATION OF DOWNSTREAM METABOLITES AND THE SUBSEQUENT ENERGY DEFICIENCY IN THE MUSCLE. HOWEVER, HOW THE MYOCYTES UTILIZE THE FUEL IS UNDEREXPLORED. PYRUVATE, THE END-PRODUCT OF GLYCOLYSIS, IS POSITIONED AT A UNIQUE METABOLIC JUNCTION THAT CAN WITNESS BOTH MITOCHONDRIAL DYSFUNCTION AND INFLAMMATION VIA TWO ENZYMATIC REACTIONS: PDH AND LDH. PYRUVATE DEHYDROGENASE (PDH) LINKS GLYCOLYSIS AND THE TRICARBOXYLIC ACID (TCA) CYCLE IN MITOCHONDRIA. LACTATE DEHYDROGENASE (LDH) ACTIVITY IS OFTEN CONSIDERED AS A MEASURE FOR GLYCOLYSIS OR ANAEROBIC RESPIRATION AND IS POSITIVELY CORRELATED WITH TISSUE INFLAMMATION. CARBON- 13 (13C) MRI WITH AN INTRAVENOUS BOLUS INJECTION OF HYPERPOLARIZED (HP) [1-13C]PYRUVATE IS A UNIQUE IMAGING METHOD FOR ESTIMATING LDH ACTIVITY AND PDH FLUX BY THE IN-VIVO PRODUCTS, [1-13C]LACTATE AND [13C]BICARBONATE, RESPECTIVELY. SINCE HYPERPOLARIZATION TECHNOLOGY IS USING STABLE ISOTOPE (NO IONIZING RADIATION) AND PYRUVATE IS A NATURAL METABOLITE, IT IS SAFE TO INJECT HP [1-13C]PYRUVATE INTO BOTH ADULT AND PEDIATRIC PATIENTS. IN THIS PROPOSAL, WE WILL INVESTIGATE MITOCHONDRIAL DYSFUNCTION AND INFLAMMATION IN DMD AND BMD PATIENTS USING HP [1- 13C]PYRUVATE MRI. THUS, THE OVERALL GOAL OF THE STUDY IS TO DEVELOP NON-INVASIVE BIOMARKERS THAT DETECT EARLY METABOLIC CHANGES ASSOCIATED WITH MYOPATHIES IN PATIENTS WITH MD. THE UNDERLYING HYPOTHESIS IS THAT METABOLIC ALTERATIONS IN MYOCARDIUM AND SKELETAL MUSCLE PRECEDE MYOPATHIES ASSOCIATED WITH DYSTROPHINOPATHY. THE SPECIFIC AIMS INCLUDE TO DEVELOP ELEVATED LACTATE PRODUCTION AS A BIOMARKER FOR MYOCARDITIS AND SKELETAL MUSCLE INFLAMMATION (AIM 1), TO DEVELOP LIMITED BICARBONATE PRODUCTION AS A BIOMARKER OF MITOCHONDRIAL DYSFUNCTION (AIM 2), AND TO ASSESS EARLY CHANGES IN LACTATE-TO-BICARBONATE RATIO IN PREDICTING MD-ASSOCIATED MYOPATHY (AIM 3). THE IMAGING BIOMARKERS WILL BE COMPARED TO CLINICAL CARDIAC PARAMETERS (E.G., VENTRICULAR EJECTION FRACTION) AND OTHER INFLAMMATORY MARKERS OR CORONARY RISK INDICATORS FROM BLOOD SAMPLES (E.G., HIGH-SENSITIVITY TROPONIN T). THE RESEARCH OUTCOME OF THE PROPOSED STUDY WILL DEVELOP IN-VIVO IMAGING BIOMARKERS THAT ASSESS METABOLIC CHARACTERISTICS OF THE HEART AND SKELETAL MUSCLE IN PATIENTS WITH MUSCULAR DYSTROPHY, AND SET A GROUNDWORK FOR CLINICAL TRANSLATION OF THIS TECHNIQUE TO MUSCULAR DYSTROPHY PATIENTS.