Mitochondrial creatine sensitivity is lost in the D2. mdx model of Duchenne muscular dystrophy and rescued by the mitochondrial-enhancing compound Olesoxime

Catherine Bellissimo , Luca Delfinis , Meghan Hughes , Patrick Turnbull , Shivam Gandhi , Sara Dibenedetto , Fasih Rahman , Peyman Tadi , Christina Amaral , Ali Dehghani , James Cobley , Joe Quadrilatero , Uwe Schlattner (1) , Christopher G.R. Perry

1 LBFA - Laboratory of Fundamental and Applied Bioenergetics = Laboratoire de bioénergétique fondamentale et appliquée

Duchenne muscular dystrophy (DMD) is associated with distinct mitochondrial stress responses. Here, we aimed to determine whether the prospective mitochondrial-enhancing compound Olesoxime, prevents early-stage mitochondrial stress in limb and respiratory muscle from D2. mdx mice using a proof-of-concept short-term regimen spanning 10–28 days of age. As mitochondrial-cytoplasmic energy transfer occurs via ATP- or phosphocreatine-dependent phosphate shuttling, we assessed bioenergetics with or without creatine in vitro. We observed that disruptions in Complex I-supported respiration and mH 2 O 2 emission in D2. mdx quadriceps and diaphragm were amplified by creatine demonstrating mitochondrial creatine insensitivity manifests ubiquitously and early in this model. Olesoxime selectively rescued or maintained creatine sensitivity in both muscles, independent of the abundance of respiration-related mitochondrial proteins or mitochondrial creatine kinase cysteine oxidation in quadriceps. Mitochondrial calcium retention capacity and glutathione were altered in a muscle-specific manner in D2. mdx but were generally unchanged by Olesoxime. Treatment reduced serum creatine kinase (muscle damage) and preserved cage hang-time, microCT-based volumes of lean compartments including whole body, hindlimb and bone, recovery of diaphragm force after fatigue, and cross-sectional area of diaphragm type IIX fiber, but reduced type I fibers in quadriceps. Grip strength, voluntary wheel-running and fibrosis were unaltered by Olesoxime. In summary, locomotor and respiratory muscle mitochondrial creatine sensitivities are lost during early stages in D2. mdx mice but are preserved by short-term treatment with Olesoxime in association with specific indices of muscle quality suggesting early myopathy in this model is at least partially attributed to mitochondrial stress.

Domaines: Sciences du Vivant [q-bio]

Catherine Bellissimo, Luca Delfinis, Meghan Hughes, Patrick Turnbull, Shivam Gandhi, et al.. Mitochondrial creatine sensitivity is lost in the D2. mdx model of Duchenne muscular dystrophy and rescued by the mitochondrial-enhancing compound Olesoxime. American Journal of Physiology - Cell Physiology, 2023, 324 (5), pp.C1141-C1157. ⟨10.1152/ajpcell.00377.2022⟩. ⟨hal-04550865⟩