Generation of reactive oxygen species (ROS) under physiological conditions is required for normal force production in skeletal muscle. However, high levels of ROS are observed during intense physical exercise and promote contractile dysfunction, resulting in muscle weakness and fatigue. There is growing evidence that sub-cellular site-specific ROS production governs the beneficial vs. damaging effects of ROS. NADPH oxidase (Nox2) is an enzyme complex that generates ROS. Ongoing work by PI has found that increased ROS generation from Nox2 during intense contractile activity contributes to fatigue. We have strong evidence that Src tyrosine kinase acts as a redox switch to activate Nox2. The central hypothesis of this proposal is that Nox2 and Src act through a feed-forward pathway leading to excessive ROS production and contractile dysfunction. We will use genetically modified mice lacking Nox2, genetically encoded site-specific redox sensors and a novel tool to measure force and Ca2+ transients simultaneously in living skeletal muscle fibers to address the following specific aims: 1. Define the mechanisms by which contractile activity increases Nox2 dependent ROS production in skeletal muscle, 2. Determine whether Src serves as a redox switch to modulate activity dependent ROS production, and 3. Assess the role of Nox2 and Src on cytosolic [Ca2+ ]i transients and force generation. The proposed research will identify the sub-cellular sites of ROS production and elucidate the signaling pathways that control ROS regulation of microdomain Ca2+ signaling in skeletal muscle. Furthermore, it will lay the foundation for the development of targeted antioxidant therapy to combat the deleterious effects of overproduction of ROS seen in muscle fatigue and disease.

Public Health Relevance

Skeletal muscle contraction is regulated by calcium inside the cell. Reactive oxygen species are also produced inside the cell. Excessive production of reactive oxygen species promotes muscle weakness and fatigue in patients with heart failure, cancer, HIV, emphysema and muscular dystrophy. Scientists working on this proposal have found that an NADPH oxidase plays an important biological role in promoting muscle weakness. The planned work will examine how local activation of NADPH oxidase leads to changes in cellular calcium and muscle weakness. The results from this study will have important implications for physical performance and disease therapy.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-MOSS-T (02))
Program Officer
Boyce, Amanda T
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Baylor College of Medicine
Schools of Medicine
United States
Zip Code
Kho, Jordan; Tian, Xiaoyu; Wong, Wing-Tak et al. (2018) Argininosuccinate Lyase Deficiency Causes an Endothelial-Dependent Form of Hypertension. Am J Hum Genet 103:276-287
Wang, Qiongling; Quick, Ann P; Cao, Shuyi et al. (2018) Oxidized CaMKII (Ca2+/Calmodulin-Dependent Protein Kinase II) Is Essential for Ventricular Arrhythmia in a Mouse Model of Duchenne Muscular Dystrophy. Circ Arrhythm Electrophysiol 11:e005682
Loehr, James Anthony; Wang, Shang; Cully, Tanya R et al. (2018) NADPH oxidase mediates microtubule alterations and diaphragm dysfunction in dystrophic mice. Elife 7:
Pal, Rituraj; Palmieri, Michela; Chaudhury, Arindam et al. (2018) Src regulates amino acid-mediated mTORC1 activation by disrupting GATOR1-Rag GTPase interaction. Nat Commun 9:4351
Brinegar, Amy E; Xia, Zheng; Loehr, James Anthony et al. (2017) Extensive alternative splicing transitions during postnatal skeletal muscle development are required for calcium handling functions. Elife 6:
Liu, Ruya; Lee, Jeongkyung; Kim, Byung S et al. (2017) Tead1 is required for maintaining adult cardiomyocyte function, and its loss results in lethal dilated cardiomyopathy. JCI Insight 2:
Palmieri, Michela; Pal, Rituraj; Nelvagal, Hemanth R et al. (2017) mTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases. Nat Commun 8:14338
Lee, Chang Seok; Hanna, Amy D; Wang, Hui et al. (2017) A chemical chaperone improves muscle function in mice with a RyR1 mutation. Nat Commun 8:14659
Pal, Rituraj; Bondar, Vitaliy V; Adamski, Carolyn J et al. (2017) Inhibition of ERK1/2 Restores GSK3? Activity and Protein Synthesis Levels in a Model of Tuberous Sclerosis. Sci Rep 7:4174
Rodney, George G; Pal, Rituraj; Abo-Zahrah, Reem (2016) Redox regulation of autophagy in skeletal muscle. Free Radic Biol Med 98:103-112

Showing the most recent 10 out of 20 publications