Impact of Aging on Skeletal Muscle Blood Flow Kinetics During Exercise

Summary

Principal Investigator: DARREN PATRICK CASEY
Abstract: PROJECT SUMMARY/ABSTRACT During dynamic exercise skeletal muscle blood flow increases rapidly and dramatically (exercise hyperemia) to meet the metabolic needs of the contracting tissue. Aging is associated with an attenuated hyperemic response during dynamic exercise. The mechanisms responsible for increasing blood flow at the onset of exercise as well as maintaining it over time in young adults involves a complex interaction between mechanical factors, the sympathetic nervous system and local metabolic and endothelial derived substances that influence vascular tone. The mechanisms responsible for the observed reductions in exercise blood flow in older humans are not completely clear. The applicant proposes two main goals: 1) to identify mechanisms contributing to the altered vasodilator responses to single muscle contractions and dynamic exercise in aging humans, and 2) to examine the effect of aging on the kinetics of skeletal muscle blood flow/vasodilation during exercise. During the K99/Mentored phase of the grant, the applicant will examine the mechanical, endothelial, and neural alterations in vascular function that occur with aging and determine how these changes relate to the attenuated rapid vasodilator response following a single muscle contraction. In the first portion of the R00/Independent phase of the grant, the applicant will examine the kinetics (rest to steady state transition) of vasodilation during rhythmic exercise and quantify the effects of aging on these responses. In the second portion of the R00 phase, the applicant evaluate whether the attenuated vasodilator response to single muscle contractions and slower kinetics of vasodilation during rhythmic exercise are similar in the upper and lower limbs of older subjects. Lastly, in the third portion of the R00 phase, the applicant will determine whether the changes in flow following single contractions and/or the kinetics of vasodilation in older humans is a result of physiological aging or related to training status. Collectively, the experiments outlined in this proposal focus on the mechanical, endothelial, and neural alterations that occur in the skeletal muscle vasculature with aging and how these changes impact blood flow in exercising muscle. Identifying the mechanisms by which blood flow to contracting muscles is altered with advancing age will help in understanding whether these changes are due to physiological age per se or a result of inactivity. During the K99/Mentored phase of the award the applicant will 1) continue to gain expertise in basic integrative physiology studies in conscious humans, and 2) continue to learn pharmacological and biochemical approaches to study the control of muscle blood flow from a mechanistic standpoint. Additionally, the candidate will gain new research skills and knowledge related to advanced cutting-edge ultrasound techniques and measures of arterial properties (specifically, Shearwave Dispersion Ultrasound Vibrometry;SDUV) under the mentorship of Dr. James Greenleaf (co-mentor). Training in an established and productive laboratory such as that of Dr. Michael Joyner along with the help of Dr. James Greenleaf at the Mayo Clinic will provide opportunities needed to achieve the goals listed above. Importantly, this training will facilitate the achievement of the applicant's long-term goal to develop an internationally-renowned independent research program in cardiovascular physiology.
Funding Period: 2011-08-01 - 2016-03-31
more information: NIH RePORT

Detail Information

Research Grants30

  1. The Shelf Live Evaluation of Investigational Dosage Forms
    Jonathan White; Fiscal Year: 2013
    ..This contract is essential for continued assurance of the quality of drugs undergoing clinical investigation for different types of cancer by Cancer Therapeutics Evaluation Program. ..
  2. Aging, Sleep Apnea, and Vascular Control During Systemic Hypoxia
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  3. Neuro-Circulatory Function in Chronic Heart Failure
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    ..The role of exercise training in modulating ROS generation and antioxidant enzymes in animals with CHF will also be investigated in this project. ..
  4. Peripheral Vasodilation in Obese Humans
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    ..Our novel findings will guide the development of novel therapeutic strategies for obesity and other diseases, including obstructive sleep apnea, metabolic syndrome and diabetes. ..
  5. Golgi-associated NO-cGMP Signaling Defect in Muscular Dystrophy
    Gail D Thomas; Fiscal Year: 2013
    ..In general, the knowledge generated by this project will be relevant to many types of muscle diseases. ..
  6. Rebuilding the Failing Heart
    Piero Anversa; Fiscal Year: 2013
    ..abstract_text> ..
  7. Lentiviral Gene Therapy for Sickle Cell Disease and Immunodeficiency Disorders
    Brian P Sorrentino; Fiscal Year: 2013
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  8. Neurovascular Control and Blood Pressure Regulation in Humans
    Michael J Joyner; Fiscal Year: 2013
    ....
  9. Mitochondrial dysfunction, oxidative damage and inflammation in claudication
    IRAKIS ILIAS PIPINOS; Fiscal Year: 2013
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  10. Skeletal muscle dysfunction in persons with chronic kidney disease
    Baback Roshanravan; Fiscal Year: 2013
    ..Specifically, it will provide a basis for future investigation of prospective associations of mitochondrial function, physical function with clinical outcomes in CKD patients. ..
  11. Molecular and Cellular Determinants of the Exercise Pressor Reflex in CHF
    Irving H Zucker; Fiscal Year: 2013
    ..Furthermore, w believe that these data will uncover new targets for therapy in CHF. ..
  12. Quantitative evaluation of skeletal muscle passive stiffness
    Sarah Eby; Fiscal Year: 2013
    ....
  13. Caloric Restricted Rodent Colony
    RICK MORIN; Fiscal Year: 2013
    ..The purpose of this project is to develop, maintain and distribute a standing colony ofaged, calorically restricted rodents ofdefined strains for use by investigators in studies of aging. ..
  14. FOREBRAIN PLASTICY IN HYPERTENSION
    Costantino Iadecola; Fiscal Year: 2013
    ..Thus, the collective scientific outcome of the Program is anticipated to be greater than the sum of its individual components. ..
  15. BLOOD PRESSURE CONTROL DURING EXERCISE IN HEART FAILURE
    DONAL S O'LEARY; Fiscal Year: 2013
    ..These longitudinally designed experiments we feel will provide compelling new information on the altered mechanisms of cardiovascular control during exercise in heart failure. ..
  16. Excitability of afferents evoking the exercise pressor reflex
    Victor Ruiz-Velasco; Fiscal Year: 2013
    ..Likewise, in muscles, whose arteries are narrowed by disease, exercise can cause excessive stimulation of the sensory nerves that reflexively activate the sympathetic nervous system muscle pain (i.e., claudication). ..
  17. Dietary Nitrate to Augment Exercise Training Benefits in DM+PAD
    Jason David Allen; Fiscal Year: 2013
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  18. Role of Thromboxane in the Exercise Pressor Reflex in Peripheral Artery Disease
    ANNA KATHERINE LEAL; Fiscal Year: 2013
    ..These studies may lead to novel treatments that could potentially increase walking tolerance in individuals suffering from peripheral artery disease and reduce the risks and pain associated with physical activity. ..
  19. NIPBL, Cohesin and Related Structural Birth Defects
    Ian D Krantz; Fiscal Year: 2013
    ..This Program outlines a plan to characterize cohesin's function in gene regulation, identify its effector genes and evaluate their role in causing isolated birth defects of the types seen in CdLS. ..
  20. MOLECULAR GENETICS OF COAGULATION DISORDERS
    David Ginsburg; Fiscal Year: 2013
    ..This Project will identify key genes in this system that should provide valuable new diagnostic tools as well as suggest novel approaches to treatment. ..
  21. Noninvasive assessment of microvascular function in aging
    Jill M Slade; Fiscal Year: 2013
    ..Our long-term goal is to establish noninvasive methods for assessing microvascular and muscle function that can be used in vascular and muscle disease detection and monitoring. ..
  22. Cellular S-nitrosothiol signaling in respiratory biology
    Lisa Palmer; Fiscal Year: 2013
    ..This program will make extensive use of intramural and extramural collaborations, as well as Program Core facilities, to make good use of our institutional strengths in S-nitrosothiol biology. ..
  23. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  24. Training-Muscle Blood Flow and Capillary Dynamics
    M Harold Laughlin; Fiscal Year: 2013
    ....
  25. Neurovascular Dysfunction and Oxidative Stress in Renal Failure
    Jeanie Park; Fiscal Year: 2013
    ..BH4 therapy may be such a novel therapeutic agent that has the potential to impact exercise tolerance, as well as decrease baseline cardiovascular risk in patients with CRF. (End of Abstract) ..
  26. Examining Vascular Regulation Following Acute Stroke
    Sandra Billinger; Fiscal Year: 2013
    ..However, before a clinical trial is undertaken, it is important and essential that one understands the role of pro-inflammatory markers and vascular function during stroke recovery. ..
  27. Low Magnitude Mechanical Stimulation to Increase Muscle Strength in Frail Adults
    THUY TIEN LE DAM; Fiscal Year: 2013
    ..The proposed studies should provide novel information about the importance of intermuscular fat in the development of disability, and could lead to new strategies for the treatment and prevention of sarcopenia. ..
  28. Cellular Senescence and Aging
    James L Kirkland; Fiscal Year: 2013
    ..Our approach will provide timely, innovative, and clinically relevant interventional results based on addressing the fundamental question of the role of cellular senescence that has remained unanswered for many years. ..
  29. Ankle dorsiflexion splinting enhances endothelial function of aged leg muscles
    JUDY M DELP; Fiscal Year: 2013
    ..In addition, a program of daily dorsiflexion splinting, if shown to improve endothelial function in healthy older sedentary subjects, could be rapidly translated to clinical populations. ..