Mitochondria and Metabolism Journal Club
Presented by Yushekia S. Woodford, MS2- June 2016

Targeting Mitochondria to Restore Failed Adaptation to Exercise in Diabetes – by Geary et al., Biochemical Society 2014

Introduction: The translational research group focuses on the problem of exercise defects in diabetes with basic research efforts in cell and rodent models as well as clinical research efforts in subjects with diabetes mellitus. The authors review the relationship between exercise and vascular function with particular interest in CREB and eNOS [endothelial NOS (nitric oxide synthase)]. Researchers place emphasis on how the signaling to CREB and eNOS regulate tissue perfusion, mitochondrial dynamics, vascular function, and exercise capacity. The group hypothesizes that restoration of eNOS/NOS dysfunction will restore cellular homeostasis and permit an optimal tissue response to an exercise training intervention.

Methods: The authors used an atherosclerosis model of LDL receptor-null mice and in vitro studies of SMCs exposed to LDL and oxLDL to show that both forms of LDL induce an acute activation of CREB. Only oxLDL leads to CREB down-regulation. In addition, they showed that SMCs exposed to a panel of non-esterified fatty acids exhibited an acute activation of CREB via PKA activation while saturated fatty acids triggered the down-regulation of CREB.
In order to analyze aortic mitochondrial protein content with exercise intervention, a mitochondrial protein expression profile in Sprague-Dawley (SD) and Spontaneous Hypertensive Heart Failure lean and obese rats with and without exercise training was established. Aortic lysates were generated from SD, SHHF lean, and SHHF obese rats. 30 micrograms of protein was run on SDS/PAGE (10% gels), transferred to nitrocellulose membranes and Western blot analysis was carried out.
The impact of NOS/eNOS on aortic mitochondrial protein content and dynamic baseline with exercise intervention was examined using eNOS deletion and NOS disruption to mimic diabetes and disrupt diabetes mitochondrial dynamics.

Results: The researchers evaluated the mitochondrial content and function in diabetic rodents and observed decreased mitochondrial protein profiles and enzyme activities. In control rats, there was a significant increase in mitochondrial protein profiles with a short-term exercise intervention. In the hypertensive or hypertensive diabetes mellitus rats, no such increase was observed.
In evaluating the impact of NOS/eNOS, researchers observed decreased CREB and PGC1α and increased expression of fission proteins and decreased expression of fusion proteins.

Discussion: The researchers’ findings shed light on their current hypothesis that diabetes mellitus-mediated vascular NOS dysfunction, as seen with exercise, contributes to failed mitochondrial plasticity and vascular dysfunction. While their work has helped reveal the roles of eNOS and nNOS. eNOS and nNOS may be a pharmacological target. However, more information regarding their exercise intervention is needed. In addition, it may be helpful to complete a western blot that analyzes all the rats on a single blot.  This review opens many avenues for future exploration.

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