Terence 2015 Abstract MiPschool Greenville 2015

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Mitochondrial dysfunction is a genetic component of ischemic tissue pathology and occurs independent of differential blood flow in the murine limb.

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Ryan TE, Schmidt CA, Reese LR, Green TD, Neufer PD, McClung JM (2015)

Event: MiPschool Greenville 2015

The cellular mechanism(s) responsible for the substantial morbidity and mortality rates of critical limb ischemia (CLI) are not known. Recent work from our group and others suggests that ischemic muscle myopathy modulates tissue necrosis and limb blood flow in a murine strain-dependent manner. Aberrant mitochondrial structure and function has been reported in the skeletal muscle of CLI patients, although these alterations have largely been described as secondary consequences. We hypothesized that alterations in mitochondrial respiration are genetically determined by parental background strain and occur independent of differential limb blood flow.

We examined mitochondrial respiration in genetically ischemia protected (BL6; n=60) and susceptible (BALB/cJ; n=60) mice. During acute limb ischemia (ALI) BALB/c mice displayed a rapid (1d) and sustained (3d, 7d) reduction (normalized to contralateral control limb; 1d: 5.0±0.9%, 3d: 9.0±3.1%, 7d: 16.3±3.3%, p<0.05 for all) in muscle mitochondrial function; whereas BL6 mice were largely protected (normalized to contralateral control limb; 1d: 77.2±12.4%, 3d: 59.5±1.7%, 7d: 64.8±20.5%, p=NS for all). Mitochondrial deficits preceded (1d) the BALB/c strain dependent reduction in limb blood flow (p<0.02 v BL6 at d3, d7). Ameroid constrictor induced sub-acute ischemia, which alleviates the immediate cessation of limb blood flow and rapid tissue necrosis of ALI, also resulted in BALB/c mitochondrial deficits (d7; 40.8±8.1% v 83.8±20.3% for BALB/c v BL6, p=0.02) and coincided with muscle myopathy. Parental strain-dependent deficits in mitochondrial respiration were verified in mitochondria isolated from healthy control mice subjected to a brief (1hr) hypoxic insult ex vivo. BALB/c mitochondrial deficits were conserved across isolated skeletal muscle (75.3±8.5% v 101.2±9.3% for BL6, p<0.01), liver (68.6±4.9% v 80.7±6.9% for BL6, p=0.18), kidney (73.6±1.9% v 85.9±1.3% for BL6, p=0.17), cardiac (84.9±5.2% v 88.9±6.07% for BL6, p=0.73), and brain mitochondria (74.4±7.5% v 100.3±6.6% for BL6, p<0.01) and rescued across all tissues in F1 (C57BL/6 X BALB/c; n=12) mice.

In this study we verify the inherent susceptibility of ischemic tissue mitochondria, particularly limb muscle, in a manner independent of differences in strain dependent blood flow and tissue necrosis. These findings lend novel insight into the unique role of genetic background on tissue bioenergetics in the clinical divergence of CLI presentations.


O2k-Network Lab: US NC Greenville Neufer PD


Labels: MiParea: Respiration 

Stress:Ischemia-reperfusion  Organism: Mouse  Tissue;cell: Heart, Skeletal muscle, Nervous system, Liver, Kidney  Preparation: Isolated mitochondria 



Event: Poster 


Affiliations

1-Dept Physiol; 2-Diabetes Obesity Inst, East Carolina Univ, Brody Med Center, Greenville, NC, USA. – ryant@ecu.edu