Poster abstracts

Poster number 3 submitted by Oluwafolajimi Adesanya

DM1 CUG repeat expression alters cardiac mitochondrial respiration and dynamics

Oluwafolajimi Adesanya (Department of Biochemistry, University of Illinois Urbana-Champaign), Pouya Nabie (Department of Biochemistry, University of Illinois Urbana-Champaign), Subhashis Natua (Department of Biochemistry, University of Illinois Urbana-Champaign), Auinash Kalsotra (Department of Biochemistry, University of Illinois Urbana-Champaign)

Abstract:
Myotonic dystrophy type I (DM1) is a multi-systemic disease characterized by debilitating muscle weakness, a wide range of metabolic derangements and fatal cardiac arrythmias.1-3 While numerous DM1-induced splicing defects of genes encoding cardiac ion channels have been linked to arrythmia development, we hypothesize that a dysregulation in cardiac ATP generating machinery may alternatively explain this DM1 phenotype. In a cardiac-specific DM1 CUG repeat expression mouse model (TRE960i;MHCrtTA), we investigated changes in mitochondrial respiration using Seahorse isolated mitochondria coupling and electron flow assays. This was followed by quantitative gene expression studies and transmission electron microscopy for morphometric analysis.

We found that cardiac CUG repeat expression induces a strong increase in mitochondrial respiration, manifesting as a multi-fold increase in basal (state II), ADP-stimulated (state III) and state IV respiration. Respiratory control ratio, however, remained unchanged, indicating that the increase in mitochondrial respiration did not translate into an increased efficiency of OXPHOS in DM1 hearts. We found a significant alteration in expression of genes involved in mitochondrial fusion-fission – Opa1, Fis1, and mitophagy – Prkn genes, suggesting dysregulated mitochondrial dynamics as a possible mechanism for the observed increase in mitochondrial respiration.

These findings were supported by transmission electron micrographs which revealed increased mean intermyofibrillary mitochondria area in DM1 hearts. Taken together, these results support our hypothesis that DM1 increases mitochondrial respiratory capacity, by altering normal mitochondrial dynamics and biogenesis. Future experiments will focus on identifying potential mechanisms involving specific DM1-dysregulated RNA-binding proteins that could explain the observed findings.

References:
1. Groh, W. J. et al. Electrocardiographic abnormalities and sudden death in myotonic dystrophy type 1. N Engl J Med 358, 2688–2697 (2008).
2. Heatwole, C. et al. Patient-reported impact of symptoms in myotonic dystrophy type 1 (PRISM-1). Neurology 79, 348–357 (2012).
3. Phillips, M. F. & Harper, P. S. Cardiac disease in myotonic dystrophy. Cardiovasc Res 33, 13–22 (1997).

Keywords: Myotonic dystrophy type 1, Mitochondria, OXPHOS