Background: Pyruvate metabolism in skeletal muscle plays an essential role for energy production and development of muscular dystrophy (MD). However, investigation of the metabolism of MD has been focused on myocardium due to its vital importance, rather than skeletal muscle. It is still unclear as to what extent energy metabolism affects muscle pathology of MD. A better understanding of the metabolic balance and the accompanied alterations in the dystrophic muscle may improve establishing therapeutic strategies for MD patients. Metabolic imaging with hyperpolarized 13C-pyruvate can assess the altered metabolism in MD in vivo.
Methods: Three groups of mice were investigated for enzyme activity and isotopomer flux analysis with an IV injection of [U-13C]pyruvate: mice with utrophin heterozygous mdx (DKO, mdx/utrn+/-), traditional mdx model, and wild-type (WT) control. In parallel, two Becker MD patients and healthy control subjects were recruited (IRB#: STU-2021-0168, STU-2022-0189, STU-2018-0227) for up to two injections of hyperpolarized pyruvate. All the in vivo MR data were acquired using a 3T MRI scanner (750w Discovery, GE Healthcare) and a SPINlabTM polarizer (GE Healthcare).
Results: The ex vivo tissue NMR analysis showed larger 13C-labeing in lactate in DKO mice compared to WT, which was consistent with the upregulated LDH activity. Conversely, lower pyruvate flux was measured in the DKO mice compared to the WT. The NMR findings were consistent with upregulated LDH and decreased PDH activities in DKO muscle (p < 0.01). Increased lactate production and decreased PDH activity could be confirmed in the MD patients as compared to the control subjects.
Conclusion: This study indicates that pyruvate metabolism is altered in skeletal muscle with MD. The skeletal muscle of MD prefers anaerobic respiration, indicated by LDH activity, to aerobic respiration, measured by PDH activity.
Acknowledgements: National Institute of Health: R01NS107409, P30DK127984, P41EB015908, S10OD018468, S10RR029119; Department of Defense: W81XWH2210485; Muscular Dystrophy Association: MDA963281; Wellstone MDCRC Trainee Fellowship Award.