Principal Investigator (Last, First): Amann, Markus ABSTRACT Patients with COPD are limited in their daily activities because of exercise limitation that can be sufficiently severe to impair simple everyday tasks. The proposed research will examine novel mechanisms that might contribute to this severe limitation in exercise tolerance and also determine how exercise tolerance might be improved. Specifically, we will assess the role of excessive respiratory muscle work, a characteristic of COPD patients, and elevated oxidative stress during exercise in this population. Additionally, we will assess whether the increased work of breathing is a significant contributor to the increased levels of oxidative stress during exercise in patients with COPD. We will a) use a mechanical ventilator in combination with a reduced density gas mixture to reduce the work of breathing during cycle exercise and b) use venous infusion of vitamin C during cycle exercise to examine the effects of both, the reduced work of breathing and the reduced oxidative stress on muscle fatigue in the exercising legs. We will use a novel combination of methods to provide a sensitive, reproducible, objective means of quantifying limb muscle fatigue. We will further examine whether these proposed effects on limb fatigue are, in part, due to blood flow and oxygen (O2) transport to the limbs and how this is influenced by the work of breathing and oxidative stress. In healthy subjects it has been shown that a reduction in respiratory muscle work increases blood flow and O2 transport to the limbs. Also in healthy subjects, we have recently revealed that increases in blood flow / O2 transport to the working legs significantly reduces muscle fatigue and improves exercise tolerance. Furthermore, it has been shown that a reduction in oxidative stress also increases blood flow / O2 delivery during exercise in older healthy individuals, however, there are currently no data on the effects of oxidative stress on limb blood flow / O2 transport in COPD patients during exercise. In view of the significantly increased work of breathing required during exercise and the substantially increased oxidative stress in COPD patients, we expect the effects of reducing the impact of these factors on limb muscle fatigue to be even greater than in healthy subjects. We propose that this research will provide new effective methods to improve exercise capacity during the rehabilitation of patients with COPD by allowing them to improve endurance of their locomotor muscles. It is anticipated that this improvement in the rehabilitation process will prevent the deterioration of muscle function which is currently prevalent in the sedentary COPD population.

Public Health Relevance

Principal Investigator (Last, First): Amann, Markus Relevance to Public Health We propose that this research will provide new effective methods to improve exercise capacity during the rehabilitation of patients with COPD by allowing them to improve endurance of their locomotor (leg) muscles. It is anticipated that this improvement in the rehabilitation process will prevent the deterioration of muscle function which is currently prevalent in the sedentary COPD population.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Transition Award (R00)
Project #
4R00HL103786-03
Application #
8598651
Study Section
Special Emphasis Panel (NSS)
Program Officer
Tigno, Xenia
Project Start
2013-03-01
Project End
2016-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
3
Fiscal Year
2013
Total Cost
$248,514
Indirect Cost
$81,959
Name
University of Utah
Department
Type
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Amann, Markus; Sidhu, Simranjit K; Weavil, Joshua C et al. (2015) Autonomic responses to exercise: group III/IV muscle afferents and fatigue. Auton Neurosci 188:19-23
Rossman, Matthew J; Garten, Ryan S; Venturelli, Massimo et al. (2014) The role of active muscle mass in determining the magnitude of peripheral fatigue during dynamic exercise. Am J Physiol Regul Integr Comp Physiol 306:R934-40
Goodall, S; Twomey, R; Amann, M et al. (2014) AltitudeOmics: exercise-induced supraspinal fatigue is attenuated in healthy humans after acclimatization to high altitude. Acta Physiol (Oxf) 210:875-88
Dempsey, Jerome A; Blain, Gregory M; Amann, Markus (2014) Are type III-IV muscle afferents required for a normal steady-state exercise hyperpnoea in humans? J Physiol 592:463-74
Sidhu, Simranjit K; Weavil, Joshua C; Venturelli, Massimo et al. (2014) Spinal ?-opioid receptor-sensitive lower limb muscle afferents determine corticospinal responsiveness and promote central fatigue in upper limb muscle. J Physiol 592:5011-24
Pollak, Kelly A; Swenson, Jeffrey D; Vanhaitsma, Timothy A et al. (2014) Exogenously applied muscle metabolites synergistically evoke sensations of muscle fatigue and pain in human subjects. Exp Physiol 99:368-80
Amann, Markus; Venturelli, Massimo; Ives, Stephen J et al. (2014) Group III/IV muscle afferents impair limb blood in patients with chronic heart failure. Int J Cardiol 174:368-75