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Research Interest:
1) Cellular and Molecular Mechanisms of Muscle Fatigue.
2) Store-Operated Calcium Channel in Muscle Cells.
3) Cellular and Molecular Mechanisms of Ca Signaling and Contractile
Function in Skeletal and Cardiac Muscles under physiopathological
conditions.
4) Application of Intact and Skinned Muscle Preparation Assays to
the understanding of E-C coupling and muscle plasticity.
Description of Research Activity:
Excitation-contraction (E-C) coupling is a fundamental signaling
transduction process within cardiac and skeletal muscle cells that
encompasses all cycles of the contractile cycle from the initial
activation of the DHP receptors to the reuptake of calcium to the
sarcoplasmic reticulum.
By using intact muscles, skinned muscle fibers and dissociated
cells from several triad-junction proteins deficient mouse strains,
we will be able to further investigate E-C coupling in skeletal
and cardiac muscles. We are particularly interested in the cellular
and molecular mechanisms underlying muscle fatigue, pathological
states and muscle plasticity in general.
The experimental methods to accomplish our goals include: mutagenesis,
molecular biology techniques, immunological and biochemical assays
of recombinant proteins, spectrofluorometer measurement of intracellular
ions, confocal microscopic imaging of intracellular and subcellular
Ca2+ movement, biophysical and electro-physiology techniques.
Publications:
Book Chapter
Creazzo, T.L, Burch, J.L. and Brotto, M.A.P. The Excitation-Contraction
Coupling in Cardiac Dysmorphogenesis. In: The Developing Heart,
Chapter 23: pp. 313-324. Lippincott-Raven Publishers, Philadelphia/New
York, 1997.
Peer-Reviewed Full Length Manuscripts
Brotto, M.A.P.; Fogaca, R.T.H.; Creazzo, T.L.; Godt, R.E.; &
Nosek, T.M. The effect of 2,3-Butanedione 2-monoxime (BDM) on Ventricular
Trabeculae from the Avian Heart. Journal of Muscle Research and
Cell Motility. 16:1-10, 1995.
Maughan, D.W., Malloy, J.E., Brotto, M.A.P and Godt, R.E. Approximating
the isometric force-calcium relation of intact frog muscle using
skinned fibers. Biophysical Journal. 69:1484-1490, 1995.
Brotto, M.A.P and Creazzo, T.L, The Excitation-Contraction coupling
in the Embryonic Chick Heart. American Journal of Physiology: 270
(Heart Circ. Physiol. 39):H518-H525, 1996.
Brotto, M.A.P & Nosek, T.M. Hydrogen peroxide disrupts Ca2+release
from the sarcoplasmic reticulum of rat skeletal muscle fibers. Journal
of Applied Physiology: 81:731-737, 1996.
Chu, T.C., Jarrett J.L., Burch, Brotto, M.A.P, Creazzo, T.L, and.
Potter, D.E. Elevation of Intracellular Concentration in rabbit
Nonpigmented ciliary Epithelial Cells by Allicin. Comparative Biochemistry
and Physiology. 115C:89-94, 1996.
Simon J.C., Godt R.E., Greene, C.H., Leatherbury, L.S., Zolotouchnikov,
V.V., Brotto, M.A.P, Copp, A. J., Kirby M.L., and Creazzo, T.L.
Neural Crest is Involved in Development of Abnormal Myocardial Function.
Journal of Molecular and Cellular Cardiology 29:2675-2685, 1997.
Creazzo, T.L, Burch, J.L., and Brotto, M.A.P. The Excitation-Contraction
Coupling in Cardiac Dysmorphogenesis. In: The Developing Heart,
Chapter 23: pp. 313-324. Lippincott-Raven Publishers, Philadelphia/New
York, 1997.
Nosek, T.M., Fogaca, R.T.H., Brotto, M.A.P, Hatcher, C.G., and
Godt, R.E. Effect of Cardiac Neural Crest Ablation on Contractile
Force and Calcium Uptake and release in Chick Heart. American Journal
of Physiology 273:H1464-H1471, 1997.
Creazzo, T.L, Brotto, M.A.P, & Burch, J.L. Excitation-contraction
coupling in the day 15 embryonic chick heart with persistent truncus
arteriosus (PTA). Pediatric Research 42:731-737, 1997.
Nosek, T.M. and Brotto, M.A.P, Oxidation Effects in Fatigue: Unphysiological
responses to "depolarization" in skinned muscle fibers
Journal of Applied Physiology. 82:2055-2056, 1997.
Shi, B., Bhat, G.K., Brotto, M.A.P, Mahesh, V.B., Nosek, T.M.
and Brann, D.W. Bradykinin Receptor Localization and Cell Signaling
Pathways Utilized by Bradykinin in the Regulation of GnRH Secretion.
Endocrinology. 140:4669-76, 1999.
Brotto, M.A.P, Nosek, C.M., Brotto, L.S., van Leyen, S.A., and
Nosek, T.M. Effects of Acute Hypoxia on the Contractility and Fatigability
of Intact and Skinned Mouse Diaphragm Muscle. Pflugers Arch 440:727-734,
2000.
Nosek, T.M., Brotto, M.A.P., Essig, D.A., Mestril, R.A., Conover,
R.C., Dillmann, W.H., and Kolbeck, R.C. Functional Properties of
Skeletal Muscle from Transgenic Animals with Upregulated Heat Shock
Protein 70, Physiological Genomics, 4:25-33, 2000.
Nagaraj, R.Y., Nosek, C.M., Brotto, M.A.P, Nosek T.M. and Ma, J.
Contractile Properties of Skeletal Muscles from Mice Lacking the
MG29 Gene. Physiological Genomics 4:43-9, 2000.
Brotto, M.A.P, van Leyen, S.A., Brotto, L.S., Nosek, C.M., Jin,
J.-P., and Nosek, T.M. Hypoxia/Fatigue-Induced Degradation of Troponin
I and Troponin C: New Insights into Physiologic Muscle Fatigue,
Pflugers Arch. 442:738-44, 2001.
Brotto, M.A.P, Nosek, T.M. and Kolbeck R.C. Influence of Aging
on the Fatigability of Isolated Mouse Skeletal Muscle. Experimental
Physiology, 87:77-82, 2002.
Jin, J.-P., Brotto, M.A.P, Hossain, M.M., Huang, Q.-Q., Brotto,
L.S., Nosek, T.M., Morton, D.H., and Crawford, T.O. Truncation by
Glu180 Nonsense Mutation Results in Complete Loss of Slow Skeletal
Muscle Troponin T in A Lethal Nemaline Myopathy. Journal of Biological
Chemistry (JBC), Jul 11;278(28):26159-65, 2003.
Brotto, M.A.P. Chronic Stress by Immobilization and Sensitivity
of the Isolated Rat Pacemaker to Isoproterenol: Roles of Corticosterone,
Neuronal Uptake and ß-Adrenergic Homogeneity. Journal of Pharmacology
and Experimental Therapeutics (JPET), Sep;306(3):1152-8, 2003.
Thomas M. Nosek, Marco A. P. Brotto, Jin, J-P, Troponin T isoforms
alters the tolerance
of transgenic mouse cardiac muscle to acidosis, Archives of Biochemistry
and
Biophysics, In Press, 2004.
Brotto, M.A.P, Mauro T. Marrelli, Leticia S. Brotto, Marcelo Jacobs-Lorena
and Thomas M. Nosek. Biochemical and functional modifications of
mammalian skeletal muscles infected with malaria, Journal of Applied
Physiology, In Revision, 2004.
Brotto, M.A.P, Nagaraj, R.Y., Brotto, L.S., Nosek, C.M., Takeshima,
H., Nosek, T.M., and Ma, J. MG29 Modulation of the ECC and Contractile
Processes in Fast-Twitch Muscles, Cell Research, Submitted, 2004.
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