Author + information
- Jason L. Guichard,
- Gloria A. Benavides,
- Scott Ballinger,
- Victor M. Darley-Usmar and
- Louis J. DellItalia
We have shown that humans with isolated mitral regurgitation and normal systolic function have significant myofibrillar degeneration, aggregates of small mitochondria, and increased formation of oxidant species within their cardiomyocytes. These findings suggest an important relationship between the cytoskeleton and mitochondria in volume overload. To determine if differences in mitochondrial genetic background can modulate volume overload disease susceptibility, a novel mitochondria-nuclear exchange (MNX) mouse model was developed in which the mitochondria (mt) from wild-type C57BL/6J (C57 WT) and C3H/HeN (C3H WT) mice have been exchanged onto the respective nuclear (n) backgrounds (C57n:C3Hmt [C57 MNX] or C3Hn:C57mt [C3H MNX]).
Cyclical stretch experiments were performed with C57 WT, C3H WT, C57 MNX, and C3H MNX isolated cardiomyocytes. Cardiomyocytes ±exposed to stretch (60 cycles per minute with 20% stretch for 3 hours) using the Flexcell® FX-5000™ Tension System (Hillsborough, NC, USA). The XF24 Extracellular Flux Analyzer (North Billerica, MA, USA) was used to measure oxygen consumption. Transmission electron microscopy (TEM) and immunohistochemistry (IHC) analyses were used for cardiomyocyte structural and ultrastructural assessment.
Mitochondrial bioenergetic analysis associated the C57 WT and C3H MNX with bioenergetic dysfunction, and was improved in the C3H WT and C57 MNX, thus demonstrating an association between C57 mtDNA and bioenergetic dysfunction after stretch. Cardiomyocyte structural and ultrastructure analysis using IHC and TEM in C57 WT and C3H MNX revealed significant disruption of the desmin cytoskeleton and extensive ultrastructure changes including mitochondrial disorganization and swelling, smaller and rounder mitochondria with a loss of electron density, and severe structural breakdown of the myofilaments and Z-lines. This phenotype was again improved with the C3H mtDNA (C3H WT and C57 MNX).
We believe that mitochondrial genetic background plays a critical role in cytoskeletal and mitochondrial structure and function in the complex response to the pathophysiological stimuli of volume overload.
Sunday, March 30, 2014, 9:45 a.m.-10:30 a.m.
Session Title: Novels Insights and Approaches to Heart Failure Mechanisms
Abstract Category: 13. Heart Failure and Cardiomyopathies: Basic
Presentation Number: 1187-206
- 2014 American College of Cardiology Foundation