Our long-term goal is to determine the role(s) of free radicals and their derivatives in regulating contractile function of limb and respiratory skeletal muscle. In Years 4-7, we propose a comprehensive investigation of NO biology in muscle that has four Specific Aims:
Aim 1. To evaluate NO production and its regulation in skeletal muscle. We postulate that NO is produced by type II muscle fibers (Hypothesis 1A) and will test this by localizing NOS among fiber populations of individual muscles and by measuring NO production in muscles with different fiber compositions. We also will test the postulate that NO production is increased by stimulating muscle to contract (Hypothesis 1B).
Aim 2. To determine NO effects on skeletal muscle function. Our data suggest that NO inhibits contractile function of unfatigued skeletal muscle (Hypothesis 2A). We will evaluate this in unfatigued muscle. Preliminary data further suggest that NO inhibits acute muscular fatigue (Hypothesis 2B) which we propose to test by altering NO levels during fatiguing contractions.
Aim 3. To evaluate cGMP as a second messenger for NO effects. We hypothesize that cGMP depresses skeletal muscle function (Hypothesis 3A) and will test this by measuring contractile changes caused by perturbing cGMP metabolism. We also postulate that NO regulates tissue cGMP levels (Hypothesis 3B) and will test this by localizing cGMP in the tissue and by measuring NO effects on cGMP.
Aim 4. To evaluate intracellular mechanism(s) of NO effects. Contractile studies suggest that calcium release may be inhibited by NO (Hypothesis 4A). We will test free radical effects on calcium release by measuring force production and calcium transients in single fibers isolated from mouse limb muscle. We also will test the hypothesis that myofilament interaction is inhibited by NO (Hypothesis 4B) by evaluating mechanically-skinned single fibers for NO effects on the calcium-force and force-velocity relationships.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL045721-04A1
Application #
2222433
Study Section
Special Emphasis Panel (ZRG2-LBPA (02))
Project Start
1992-07-01
Project End
1999-05-31
Budget Start
1995-07-01
Budget End
1996-05-31
Support Year
4
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Andrews, Jessica L; Zhang, Xiping; McCarthy, John J et al. (2010) CLOCK and BMAL1 regulate MyoD and are necessary for maintenance of skeletal muscle phenotype and function. Proc Natl Acad Sci U S A 107:19090-5
Reid, Michael B (2008) Free radicals and muscle fatigue: Of ROS, canaries, and the IOC. Free Radic Biol Med 44:169-79
Smith, Melissa A; Reid, Michael B (2006) Redox modulation of contractile function in respiratory and limb skeletal muscle. Respir Physiol Neurobiol 151:229-41
Gong, Ming C; Arbogast, Sandrine; Guo, Zhenheng et al. (2006) Calcium-independent phospholipase A2 modulates cytosolic oxidant activity and contractile function in murine skeletal muscle cells. J Appl Physiol 100:399-405
Matuszczak, Yves; Farid, Mehran; Jones, Jeffrey et al. (2005) Effects of N-acetylcysteine on glutathione oxidation and fatigue during handgrip exercise. Muscle Nerve 32:633-8
Tang, Wei; Ingalls, Christopher P; Durham, William J et al. (2004) Altered excitation-contraction coupling with skeletal muscle specific FKBP12 deficiency. FASEB J 18:1597-9
Matuszczak, Yves; Arbogast, Sandrine; Reid, Michael B (2004) Allopurinol mitigates muscle contractile dysfunction caused by hindlimb unloading in mice. Aviat Space Environ Med 75:581-8
Arbogast, Sandrine; Reid, Michael B (2004) Oxidant activity in skeletal muscle fibers is influenced by temperature, CO2 level, and muscle-derived nitric oxide. Am J Physiol Regul Integr Comp Physiol 287:R698-705
Kumar, Ashok; Chaudhry, Imran; Reid, Michael B et al. (2002) Distinct signaling pathways are activated in response to mechanical stress applied axially and transversely to skeletal muscle fibers. J Biol Chem 277:46493-503
Reid, Michael B; Lannergren, Jan; Westerblad, Hakan (2002) Respiratory and limb muscle weakness induced by tumor necrosis factor-alpha: involvement of muscle myofilaments. Am J Respir Crit Care Med 166:479-84

Showing the most recent 10 out of 36 publications