James G. Tidball, Ph.D.

Work Address:
Terasaki Life Science Building
Molecular, Cellular & Integrative Physiology Program
UCLA
Los Angeles, CA 90095 Dept of Pathology and Laboratory Medicine
UCLA
Los Angeles, CA 90095

Affiliations
Affiliations
Distinguished Professor, Integrative Biology and Physiology, Pathology and Laboratory Medicine
Member, Brain Research Institute
Research Interests
Much of the research in my lab concerns the cell biology of muscle disease. We are particularly interested in the pathophysiology of muscular dystrophy that is caused by null mutations of the gene that encodes the membrane associated protein called dystrophin. Loss of dystrophin from humans causes the lethal, progressive disease called Duchenne muscular dystrophy (DMD). Although loss of dystrophin is the primary cause of DMD, the resulting muscle pathology is difficult to interpret in the simple context of loss of a single structural protein. Instead, current evidence tells us that the secondary loss of other, dystrophin-associated proteins is important in causing many of the pathological features of the disease. One of these dystrophin-associated proteins, called nitric oxide synthase (NOS), produces the important regulatory molecule NO, and its loss can result in misregulation of many vital processes and thereby contribute to the pathology of muscular dystrophy. Much of our current work is directed toward understanding the functions of NO in muscle and the relationships between NO defects and muscular dystrophy. We have also learned through our recent studies that the immune system contributes importantly to promoting the pathology of muscular dystrophy. We have found that both lymphoid and myeloid cells increase the death of dystrophic muscle, which suggests that immune-based therapeutics may provide a new approach to treating muscular dystrophy. Our continuing work on this project is directed toward elucidating the mechanisms through which the immune system, especially myeloid cells, causes death of dystrophic muscle. In addition, we are exploring the possibility that other subpopulations of myeloid cells may also promote regeneration of injured tissue, and provide insights into new therapeutic strategies.
Biography

Interactions between skeletal muscle and the immune system. A major project in our lab concerns the pathophysiology of muscular dystrophy (dystrophinopathy). Our research has shown that the immune system plays an important role in influencing the severity of muscular dystrophy, and that immune-based interventions can significantly reduce dystrophic muscle pathology and promote muscle regeneration. Our continuing efforts are directed toward identifying the key effector cells and molecules involved in influencing the course of the disease, and examining the interplay between those effectors. Our technical approaches include the generation and analysis of transgenic, dystrophic mice so that the effects of increased or decreased expression of selected effector molecules can be assessed. We also examine the systemic effects of experimental depletions of selected immune cell populations and the efficacy of selected, pharmaceutical interventions on the progress of the disease. In other studies, we are studying the mechanisms through which the immune system influences the wasting of skeletal muscle that occurs during aging, a process called sarcopenia. We are particularly interested in identifying the mechanisms through which specific populations of myeloid cells affect muscle wasting and regeneration, and identifying strategies to slow the wasting process.

Publications

A selected list of publications:

Wang Ying, Wehling-Henricks Michelle, Samengo Giuseppina, Tidball James G   Increases of M2a macrophages and fibrosis in aging muscle are influenced by bone marrow aging and negatively regulated by muscle-derived nitric oxide Aging Cell, 2015; 14(4): 678-88.
Tidball, J.G. and S. Welc   Macrophage-derived IGF-1 is a potent coordinator of myogenesis and inflammation in regenerating muscle, Molecular Therapy, 2015; 23: 1134-1135.
Tidball James G, Wehling-Henricks Michelle   Shifts in macrophage cytokine production drive muscle fibrosis Nature Medicine, 2015; 21(7): 665-6.
Tidball James G, Wehling-Henricks Michelle   Nitric oxide synthase deficiency and the pathophysiology of muscular dystrophy The Journal of Physiology, 2014; 592(Pt 21): 4627-4638.
Tidball James G, Bertoni Carmen   Purloined mechanisms of bacterial immunity can cure muscular dystrophy Cell Metabolism, 2014; 20(6): 927-9.
Villalta S Armando, Rosenthal Wendy, Martinez Leonel, Kaur Amanjot, Sparwasser Tim, Tidball James G, Margeta Marta, Spencer Melissa J, Bluestone Jeffrey A   Regulatory T cells suppress muscle inflammation and injury in muscular dystrophy Science Translational Medicine, 2014; 6(258): 258ra142.
Tidball James G, Dorshkind Kenneth, Wehling-Henricks Michelle   Shared signaling systems in myeloid cell-mediated muscle regeneration Development (Cambridge, England), 2014; 141(6): 1184-96.
Samengo Giuseppina, Avik Anna, Fedor Brian, Whittaker Daniel, Myung Kyu H, Wehling-Henricks Michelle, Tidball James G   Age-related loss of nitric oxide synthase in skeletal muscle causes reductions in calpain S-nitrosylation that increase myofibril degradation and sarcopenia Aging Cell, 2012; 11(6): 1036-45.
Deng Bo, Wehling-Henricks Michelle, Villalta S Armando, Wang Ying, Tidball James G   IL-10 triggers changes in macrophage phenotype that promote muscle growth and regeneration Journal of immunology (Baltimore, Md. : 1950), 2012; 189(7): 3669-80.
Villalta, S.A., Deng, B., Rinaldi, C., Wehling-Henricks, M. and J. G. Tidball   IFNγ promotes muscle damage in the mdx mouse model of Duchenne muscular dystrophy by suppressing M2 macrophage activation and inhibiting muscle cell proliferation, J. Immunol, 2011; 187: 5419-5428 .
Tidball James G   Mechanisms of muscle injury, repair, and regeneration Comprehensive Physiology, 2011; 1(4): 2029-62.
Wehling-Henricks, M. and J.G. Tidball   Neuronal nitric oxide synthase-rescue of dystrophin/utrophin double knockout mice does not require nNOS localization to the cell membrane, PLoS One , 2011; 6: e25071.
Sakellariou, G.K., Pye, D., Vasilaki, A., Zibrik, L., Palomero, J., Kabayo, T., McArdle, F., Van Remmen, H., Richardson, A., Tidball, J.G., McArdle, A. and M. J. Jackson   Role of superoxide-nitric oxide interactions in the accelerated age-related loss of muscle mass in mice lacking Cu,Zn superoxide dismutase, Aging Cell , 2011; 10: 749-760.
Wehling-Henricks, M., M. C. Jordan, T. Gotoh, W. W. Grody, K. P. Roos and J. G. Tidball   Arginine metabolism by macrophages promotes cardiac and muscle fibrosis in mdx muscular dystrophy, PLoS One, 2010; 5(5): e10763. doi:10.1371/journal.pone.0010763.
Tidball, J.G. and S.A. Villalta   Interactions between muscle and the immune system regulate muscle growth and regeneration, Amer. J. Physiol, 2010; 298: R1173-1187.
Perez Antonio L, Bachrach Estanislao, Illigens Ben M W, Jun Susan J, Bagden Eric, Steffen Leta, Flint Alan, McGowan Francis X, Del Nido Pedro, Montecino-Rodriguez Enca, Tidball James G, Kunkel Louis M   CXCR4 enhances engraftment of muscle progenitor cells Muscle & nerve, 2009; 40(4): 562-72.
Tidball, J.G. and M. Wehling-Henricks   Inflammatory mechanisms in genetic neuromuscular disorders, Inflammatory and autoimmune disorders of the nervous system in children, 2009; 455-479.
Wehling-Henricks, M., M. Oltmann, C. Rinaldi, K. H. Myung, and J. G. Tidball   Loss of positive allosteric interactions between neuronal nitric oxide synthase and phosphofructokinase contributes to defects in glycolysis and increased fatigability in muscular dystrophy, Human Molecular Genetics, 2009; 18: 3439-3451.
Deng, B., D. Glanzman and J.G. Tidball   Nitric oxide generated by muscle corrects defects in hippocampal neurogenesis and neural differentiation caused by muscular dystrophy, Journal of Physiology, 2009; 587: 1769-1778.
Tidball, J.G. and S.A. Villalta   Nitric oxide may prompt calcium leakage in dystrophic muscle, Nature Medicine, 2009; 15: 243-244.
Villalta, S.A., H.X. Nguyen, B. Deng, T. Gotoh and J.G. Tidball   Shifts in macrophage phenotypes and macrophage competition for arginine metabolism affect the severity of muscle pathology in muscular dystrophy, Human Molecular Genetics, 2009; 18: 482-496.
Tidball, J.G.   Inflammation in skeletal muscle regeneration, Skeletal muscle repair and regeneration, 2008; 243-268.
Wehling-Henricks, M., Sokolow, S., Lee, J.J., Myung, K.H., Villalta, A., and J.G. Tidball   Major basic protein-1 promotes fibrosis of dystrophic muscle and attenuates the cellular immune response in muscular dystrophy, Human Molecular Genetics, 2008; 17:2280-2292: .
Hao, M., K. Akrami, K. Wei, C. De Diego, N. Che, J.H. Ku, J.G. Tidball, M.C. Graves, P.B. Shieh and F. Chen   Muscleblind-like 2 (Mbnl2) -deficient mice as a model for myotonic dystrophy, Developmental Dynamics, 2008; 237: 403-410.
Acharyya, S., S.A. Villalta, N. Bakkar, T. Bupha-Intr, P.M.L. Janssen, M. Carathers, M. Karin, Z. Li, A. Beg, S. Ghosh, Z. Sahenk, M. Weinstein, K.L. Gardner, J.A. Rafael-Fortney, J.G. Tidball, A.S. Baldwin and D.C. Guttridge   IKK/NF-kB signaling interplay in macrophages and myofibers promotes muscle wasting in Duchenne muscular dystrophy, Journal of Clinical Investigation, 2007; 117: 889-901.
Acharyya Swarnali, Villalta S Armando, Bakkar Nadine, Bupha-Intr Tepmanas, Janssen Paul M L, Carathers Micheal, Li Zhi-Wei, Beg Amer A, Ghosh Sankar, Sahenk Zarife, Weinstein Michael, Gardner Katherine L, Rafael-Fortney Jill A, Karin Michael, Tidball James G, Baldwin Albert S, Guttridge Denis C   Interplay of IKK/NF-kappaB signaling in macrophages and myofibers promotes muscle degeneration in Duchenne muscular dystrophy The Journal of clinical investigation, 2007; 117(4): 889-901.
Tidball, J.G. and M. Wehling-Henricks   Macrophages promote muscle membrane repair and muscle fiber growth and regeneration during modified muscle loading in mice in vivo, Journal of Physiology, 2007; 578.1: 327-336.
Tidball James G, Wehling-Henricks Michelle   Macrophages promote muscle membrane repair and muscle fibre growth and regeneration during modified muscle loading in mice in vivo The Journal of physiology, 2007; 578(Pt 1): 327-36.
Pfister, K., J. Radons, J.G. Tidball, M. Pfeifer, L. Freitag, H-J. Feldmann, V. Milani, R. Issels and G. Multhoff   Patient survival by Hsp70 membrane-phenotype: association with different routes of metastasis, Cancer, 2007; 110: 926-35.
Tidball James G, Wehling-Henricks Michelle   The role of free radicals in the pathophysiology of muscular dystrophy Journal of applied physiology (Bethesda, Md. : 1985), 2007; 102(4): 1677-86.
Wehling-Henricks, M Jordan, MC Roos, KP Deng, B Tidball, JG   Cardiomyopathy in dystrophin-deficient hearts is prevented by expression of a neuronal nitric oxide synthase transgene in the myocardium Human Molecular Genetics, 2005; 14(14): 1921-33.
Tidball, JG Wehling-Henricks, M   Damage and inflammation in muscular dystrophy: potential implications and relationships with autoimmune myositis Current Opinion in Rheumatology, 2005; 17(6): 707-13.
Tidball, JG   Inflammatory processes in muscle injury and repair American Journal of Physiology, 2005; 288(2): R345-53.
Tidball James G   Inflammatory processes in muscle injury and repair American journal of physiology. Regulatory, integrative and comparative physiology, 2005; 288(2): R345-53.
Tidball James G   Mechanical signal transduction in skeletal muscle growth and adaptation Journal of applied physiology (Bethesda, Md. : 1985), 2005; 98(5): 1900-8.
Nguyen, HX Lusis, AJ Tidball, JG   Null mutation of myeloperoxidase in mice prevents mechanical activation of neutrophil lysis of muscle cell membranes in vitro and in vivo Journal of Physiology, 2005; 565(Pt 2): 403-13.
Shiao, T Fond, A Deng, B Wehling-Henricks, M Adams, ME Froehner, SC Tidball, JG   Defects in neuromuscular junction structure in dystrophic muscle are corrected by expression of a NOS transgene in dystrophin-deficient muscles, but not in muscles lacking alpha- and beta1-syntrophins Human Molecular Genetics, 2004; 13(17): 1873-84.
Tidball, JG Wehling-Henricks, M   Evolving therapeutic strategies for Duchenne muscular dystrophy: targeting downstream events Pediatric Research, 2004; 56(6): 831-41.
Tidball, JG Wehling-Henricks, M   Expression of a NOS transgene in dystrophin-deficient muscle reduces muscle membrane damage without increasing the expression of membrane-associated cytoskeletal proteins Molecular Genetics and Metabolism, 2004; 82(4): 312-20.
Kramerova, I Kudryashova, E Tidball, JG Spencer, MJ   Null mutation of calpain 3 (p94) in mice causes abnormal sarcomere formation in vivo and in vitro Human Molecular Genetics, 2004; 13(13): 1373-88.
Wehling-Henricks, M Lee, JJ Tidball, JG   Prednisolone decreases cellular adhesion molecules required for inflammatory cell infiltration in dystrophin-deficient skeletal muscle Neuromuscular Disorders, 2004; 14(8-9): 483-90.
Nguyen, HX Tidball, JG   Expression of a muscle-specific, nitric oxide synthase transgene prevents muscle membrane injury and reduces muscle inflammation during modified muscle use in mice Journal of Physiology, 2003; 550(Pt 2): 347-56.
Nguyen, HX Tidball, JG   Interactions between neutrophils and macrophages promote macrophage killing of rat muscle cells in vitro Journal of Physiology, 2003; 547(Pt 1): 125-32.
Nguyen, HX Tidball, JG   Null mutation of gp91phox reduces muscle membrane lysis during muscle inflammation in mice Journal of Physiology, 2003; 553(Pt 3): 833-41.
Tidball, J.G. and M.J. Spencer   Skipping along to new gene therapeutics for muscular dystrophy, Nature Medicine, 2003; 9: 997-998.
Tidball, J.G. and Spencer, M.   Expression of a calpastatin transgene slows muscle wasting and obviates changes in myosin isoform expression during murine muscle disuse Journal of Physiology, 2002; 545(Pt 3): 819-28.
Tidball, JG   Interactions between muscle and the immune system during modified musculoskeletal loading Clinical Orthopaedics and Related Research, 2002; 403S(403 Suppl): S100-9.
Wehling, M., Spencer, M. and J.G. Tidball   A nitric oxide synthase transgene ameliorates muscular dystrophy in mdx mice Journal of Cell Biology, 2001; 155(1): 123-31.
Spencer, MJ Tidball, JG   Do immune cells promote the pathology of dystrophin-deficient myopathies? Neuromuscular Disorders, 2001; 11(6-7): 556-64.
Spencer, MJ Montecino-Rodriguez, E Dorshkind, K Tidball, JG   Helper (CD4(+)) and cytotoxic (CD8(+)) T cells promote the pathology of dystrophin-deficient muscle Clinical Immunology , 2001; 98(2): 235-43.
Frenette, J Cai, B Tidball, JG   Complement activation promotes muscle inflammation during modified muscle use American Journal of Pathology, 2000; 156(6): 2103-10.
Zhu, X Hadhazy, M Wehling, M Tidball, JG McNally, EM   Dominant negative myostatin produces hypertrophy without hyperplasia in muscle FEBS Letters, 2000; 474(1): 71-5.
Cai, B Spencer, MJ Nakamura, G Tseng-Ong, L Tidball, JG   Eosinophilia of dystrophin-deficient muscle is promoted by perforin-mediated cytotoxicity by T cell effectors American Journal of Pathology, 2000; 156(5): 1789-96.
Wehling, M Cai, B Tidball, JG   Modulation of myostatin expression during modified muscle use FASEB Journal, 2000; 14(1): 103-10.
Koh, TJ Tidball, JG   Nitric oxide inhibits calpain-mediated proteolysis of talin in skeletal muscle cells American Journal of Physiology, 2000; 279(3): C806-12.
Koh, TJ Tidball, JG   Nitric oxide synthase inhibitors reduce sarcomere addition in rat skeletal muscle Journal of Physiology, 1999; 519 Pt 1: 189-96.
Tidball, JG Spencer, MJ Wehling, M Lavergne, E   Nitric-oxide synthase is a mechanical signal transducer that modulates talin and vinculin expression Journal of Biological Chemistry , 1999; 274(46): 33155-60.
Tidball, JG Lavergne, E Lau, KS Spencer, MJ Stull, JT Wehling, M   Mechanical loading regulates NOS expression and activity in developing and adult skeletal muscle American Journal of Physiology, 1998; 275(1 Pt 1): C260-6.
Spencer, MJ Walsh, CM Dorshkind, KA Rodriguez, EM Tidball, JG   Myonuclear apoptosis in dystrophic mdx muscle occurs by perforin-mediated cytotoxicity Journal of Clinical Investigation, 1997; 99(11): 2745-51.
Albrecht, DE Tidball, JG   Platelet-derived growth factor-stimulated secretion of basement membrane proteins by skeletal muscle occurs by tyrosine kinase-dependent and -independent pathways Journal of Biological Chemistry, 1997; 272(4): 2236-44.
Chang, W., S. Iannaccone, K. Lau, B. Masters, T. McCabe K. McMillan, R. Padre, M.J. Spencer, J.G. Tidball and J.T. Stull   Neuronal nitric oxide synthase and dystrophin-deficient muscular dystrophy, Proc. Natl. Acad. Sci. USA, 1996; 93: 9142-47.
Tidball James G   Regulation of muscle growth and regeneration by the immune system Nature Reviews. Immunology, 2017; 17(3): 165-178.
Chadwick Jessica A, Swager Sarah A, Lowe Jeovanna, Welc Steven S, Tidball James G, Gomez-Sanchez Celso E, Gomez-Sanchez Elise P, Rafael-Fortney Jill A   Myeloid cells are capable of synthesizing aldosterone to exacerbate damage in muscular dystrophy Human Molecular Genetics, 2016; 25(23): 5167-5177.
Wehling-Henricks Michelle, Li Zhenzhi, Lindsey Catherine, Wang Ying, Welc Steven S, Ramos Julian N, Khanlou NĂ©gar, Kuro-O Makoto, Tidball James G   Klotho gene silencing promotes pathology in the mdx mouse model of Duchenne muscular dystrophy Human Molecular Genetics, 2016; 25(12): 2465-2482.
Wehling-Henricks Michelle, Welc Steven S, Samengo Guiseppina, Rinaldi Chiara, Lindsey Catherine, Wang Ying, Lee Jeongyoon, Kuro-O Makoto, Tidball James G   Macrophages escape Klotho gene silencing in the mdx mouse model of Duchenne muscular dystrophy and promote muscle growth and increase satellite cell numbers through a Klotho-mediated pathway Human Molecular Genetics, 2018; 27(1): 14-29.
Tidball James G, Welc Steven S, Wehling-Henricks Michelle   Immunobiology of Inherited Muscular Dystrophies Comprehensive Physiology, 2018; 8(4): 1313-1356.
Wang Ying, Welc Steven S, Wehling-Henricks Michelle, Tidball James G   Myeloid cell-derived tumor necrosis factor-alpha promotes sarcopenia and regulates muscle cell fusion with aging muscle fibers Aging cell, 2018; 8(4): e12828.
Wang Ying, Wehling-Henricks Michelle, Welc Steven S, Fisher Allison L, Zuo Qun, Tidball James G   Aging of the immune system causes reductions in muscle stem cell populations, promotes their shift to a fibrogenic phenotype, and modulates sarcopenia FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2019; 8(4): fj201800973R.