Skeletal muscles produce reactive oxygen species (ROS) in response to a variety of stress stimuli, including thermal stress, osmotic stress, intense stimulation and hypoxia. These signals appear to be functionally significant but do not cause injury or damage under most normal physiologic conditions. We hypothesize that ROS, in this setting, play important roles in signaling networks designed to assist cells to withstand stress. The focus of the current proposal will be on the ROS produced in the transition from high to low O2 in skeletal muscle. This phenomenon is coincident with the hypoxia-induced shift in the redox state of the cell (NADH/NAD+), but we do not know if the signal arises from changes in redox or some other hypoxia- induced cellular response. We also do not know the sub-cellular origins of this signal or what phenotype produces it.
AIM 1 of the proposal will identify the primary cellular and subcellular origins of ROS formation produced during metabolic stress and it will determine the sensitivity of the ROS-generating system to changes in PO2 vs. shifts in NADH/NAD+. To address this aim we have designed new imaging methods, including multiphoton and fluorescence lifetime, and a new fluorescent probe for localization of superoxide close to membranes. We will also determine the critical stimulus modality and intensity by measuring, and independently manipulating PO2 and cell redox state.
In AIM 2, we will study the functional significance of hypoxia-induced ROS. We hypothesize that stress-induced ROS promotes energy mobilization and inhibits energy expenditure. First, we will evaluate the potential role of AMP-dependent protein kinase and glycolytic flux as a possible target for stress-induced ROS. Second, we will determine how ROS influences the relationships between Ca+2 release and force and the potential roles ROS and cell redox state have in altering Ca+2-induced force. This basic science investigation will give new insights into fundamental skeletal muscle biology that will have applications to a variety of muscle disorders related to O2 transport limitation. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL053333-11
Application #
7173768
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Harabin, Andrea L
Project Start
1994-12-01
Project End
2007-09-30
Budget Start
2007-02-01
Budget End
2007-09-30
Support Year
11
Fiscal Year
2007
Total Cost
$287,911
Indirect Cost
Name
Ohio State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Welc, Steven S; Clanton, Thomas L (2013) The regulation of interleukin-6 implicates skeletal muscle as an integrative stress sensor and endocrine organ. Exp Physiol 98:359-71
Welc, Steven S; Phillips, Neil A; Oca-Cossio, Jose et al. (2012) Hyperthermia increases interleukin-6 in mouse skeletal muscle. Am J Physiol Cell Physiol 303:C455-66
Clanton, Thomas L; Levine, Sanford (2009) Respiratory muscle fiber remodeling in chronic hyperinflation: dysfunction or adaptation? J Appl Physiol 107:324-35
Clanton, T L; Klawitter, P F (2001) Invited review: Adaptive responses of skeletal muscle to intermittent hypoxia: the known and the unknown. J Appl Physiol 90:2476-87