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035 a| (Sirsi) o902735233;

035 a| (OCoLC)902735233;

049 a| EREE;

090 a| QH634.5;

100 1 a| Lark, Daniel Stephen,e| author.?| UNAUTHORIZED;

245 10 a| Novel mechanisms governing skeletal muscle mitochondrial bioenergetics :b| OXPHOS efficiency and cAMP/PKA signaling /c| by Daniel Stephen Lark.;

246 1 i| title from signature pagea| Novel mechanisms governing the regulation of mitochondrial bioenergetics : OXPHOS efficiency and cAMP/PKA signaling;

264 1 a| [Greenville, N.C.] :b| [East Carolina University],c| 2014.;

300 a| 109 pages :b| illustrations (some color);

336 a| textb| txt2| rdacontent;

337 a| computerb| c2| rdamedia;

338 a| online resourceb| cr2| rdacarrier;

347 a| text fileb| PDFc| 3.82Mb2| rda;

538 a| System requirements: Adobe Reader.;

538 a| Mode of access: World Wide Web.;

502 b| Ph.D.c| East Carolina Universityd| 2014.;

500 a| Presented to the faculty of the Department of Kinesiology.;

500 a| Advisor: P. Darrell Neufer.;

500 a| Title from PDF t.p. (viewed March 18, 2015).;

520 3 a| Understanding the regulation of cellular metabolism is paramount to treating the growing prevalence of metabolic disease worldwide. In cellular metabolism, mitochondrial oxidative phosphorylation (OXPHOS) plays a key role as it is a primary source of energy and the governor of cellular redox homeostasis. A fundamental aspect of mitochondrial function is that cellular metabolic demand requires a corresponding increase in flux through OXPHOS; however, the regulation of OXPHOS is incompletely understood. Herein, two hypotheses were tested: 1) OXPHOS efficiency increases as a function of metabolic demand to allow mitochondria to maximize ATP synthesis at a given level of O₂ flux and 2) that OXPHOS is regulated by cAMP/PKA signaling within skeletal muscle mitochondria. First, in permeabilized myofibers (PmFBs) from mouse skeletal muscle and myocardium, the data provided herein demonstrate that OXPHOS efficiency increases from ~20% to >70% from resting [ADP] to [ADP] found during exhaustive exercise in skeletal muscle, whereas [ADP] in the myocardium remains static (at ~75-100 [mu]M) regardless of workload. Importantly, in the presence of small changes in [ADP] (e.g. 5-20 [mu]M), ATP synthesis increased independent of an increase in JO₂, suggesting that skeletal muscle mitochondria can accommodate increased metabolic demand without a requisite increase in O₂ flux, suggesting a decrease in proton leak. Second, it was demonstrated that tricarboxylic acid (TCA) cycle flux alone is insufficient to increase cAMP levels in isolated skeletal muscle mitochondria. However, pharmacological inhibition of PKA impairs a multitude of mitochondrial function outcomes in both liver and skeletal muscle that summarily implicate Complex I as a primary target. In conclusion, given the absolute necessity for coupled OXPHOS in the maintenance of energy homeostasis and the variety of diseases linked to decreased Complex I activity, the findings provided herein not only advance our current knowledge of mitochondrial bioenergetics, but provide a multitude of opportunities for future investigations.;

504 a| Includes bibliographical references.;

650 0 a| Cell metabolism.=| ^A6537;

650 0 a| Metabolismx| Disorders.=| ^A804;

650 0 a| Homeostasis.=| ^A7893;

650 0 a| Mitochondria.=| ^A434;

650 0 a| Bioenergetics.=| ^A4260;

650 0 a| Phosphorylation.=| ^A4262;

653 a| Physiology;

653 a| Health sciences;

653 a| Kinesiology;

700 1 a| Neufer, P. Darrell,e| degree supervisor.?| UNAUTHORIZED;

710 2 a| East Carolina University.b| Department of Kinesiology.?| UNAUTHORIZED;

856 40 z| Access via ScholarShipu| http://hdl.handle.net/10342/4694;

949 o| jgml;

994 a| C0b| ERE;

596 a| 1 4;

998 a| 3716373;

999 a| CLICK ON WEB ADDRESSw| ASISc| 1i| 3716373-1001l| JNETm| JOYNERr| Ys| Yt| JNE3ETDu| 2/4/2015x| ETDz| JERESOURCE;

999 a| CLICK ON WEB ADDRESSw| ASISc| 1i| 3716373-2001l| HSLELECm| HSLr| Ys| Yt| HEETDu| 2/4/2015x| ETDz| HERESOURCE;

Novel mechanisms governing skeletal muscle mitochondrial bioenergetics : OXPHOS efficiency and cAMP/PKA signaling / by Daniel Stephen Lark.

Author/creator	Lark, Daniel Stephen author.
Other author	Neufer, P. Darrell, degree supervisor.
Other author	East Carolina University. Department of Kinesiology.
Format	Theses and dissertations
Publication	[Greenville, N.C.] : [East Carolina University], 2014.
Description	109 pages : illustrations (some color)
Supplemental Content	Access via ScholarShip
Subjects	Cell metabolism. Metabolism--Disorders. Homeostasis. Mitochondria. Bioenergetics. Phosphorylation.

Variant title	title from signature page Novel mechanisms governing the regulation of mitochondrial bioenergetics : OXPHOS efficiency and cAMP/PKA signaling
Summary	Understanding the regulation of cellular metabolism is paramount to treating the growing prevalence of metabolic disease worldwide. In cellular metabolism, mitochondrial oxidative phosphorylation (OXPHOS) plays a key role as it is a primary source of energy and the governor of cellular redox homeostasis. A fundamental aspect of mitochondrial function is that cellular metabolic demand requires a corresponding increase in flux through OXPHOS; however, the regulation of OXPHOS is incompletely understood. Herein, two hypotheses were tested: 1) OXPHOS efficiency increases as a function of metabolic demand to allow mitochondria to maximize ATP synthesis at a given level of O₂ flux and 2) that OXPHOS is regulated by cAMP/PKA signaling within skeletal muscle mitochondria. First, in permeabilized myofibers (PmFBs) from mouse skeletal muscle and myocardium, the data provided herein demonstrate that OXPHOS efficiency increases from ~20% to >70% from resting [ADP] to [ADP] found during exhaustive exercise in skeletal muscle, whereas [ADP] in the myocardium remains static (at ~75-100 [mu]M) regardless of workload. Importantly, in the presence of small changes in [ADP] (e.g. 5-20 [mu]M), ATP synthesis increased independent of an increase in JO₂, suggesting that skeletal muscle mitochondria can accommodate increased metabolic demand without a requisite increase in O₂ flux, suggesting a decrease in proton leak. Second, it was demonstrated that tricarboxylic acid (TCA) cycle flux alone is insufficient to increase cAMP levels in isolated skeletal muscle mitochondria. However, pharmacological inhibition of PKA impairs a multitude of mitochondrial function outcomes in both liver and skeletal muscle that summarily implicate Complex I as a primary target. In conclusion, given the absolute necessity for coupled OXPHOS in the maintenance of energy homeostasis and the variety of diseases linked to decreased Complex I activity, the findings provided herein not only advance our current knowledge of mitochondrial bioenergetics, but provide a multitude of opportunities for future investigations.
General note	Presented to the faculty of the Department of Kinesiology.
General note	Advisor: P. Darrell Neufer.
General note	Title from PDF t.p. (viewed March 18, 2015).
Dissertation note	Ph.D. East Carolina University 2014.
Bibliography note	Includes bibliographical references.
Technical details	System requirements: Adobe Reader.
Technical details	Mode of access: World Wide Web.

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Novel mechanisms governing skeletal muscle mitochondrial bioenergetics : OXPHOS efficiency and cAMP/PKA signaling / by Daniel Stephen Lark.

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