Research in the Tidball lab is directed toward understanding processes that regulate skeletal muscle wasting and regeneration. Exploring the mechanisms through which the immune system can modulate skeletal muscle wasting, injury, regeneration and growth is a particular focus of the lab. Discoveries in the Tidball lab over the past 15 years have shown that immune cells, especially myeloid cells, play a major role in modulating muscle injury and repair that occur in chronic, muscle wasting diseases and following acute injuries. For example, their findings have shown that macrophages and eosinophils are key effector cells in the pathogenesis of Duchenne muscular dystrophy. Ongoing investigations in the lab are revealing the identity of specific molecules released by myeloid cells that promote muscular dystrophy. However, recent findings in the lab have also shown that regulatory interactions between cytotoxic, M1 macrophages in dystrophic muscle and anti-inflammatory, M2a macrophages are important in regulating the balance between the death of dystrophic muscle and regenerative processes. This work shows that the experimental manipulation of the balance between the functions of M1 and M2a macrophages can affect the severity of muscular dystrophy, suggesting that manipulation of macrophage phenotype in vivo may have potential therapeutic value for the treatment of the disease. Other investigations in the Tidball lab concern the proteolytic mechanisms that contribute to sarcopenia, the process through which muscle wasting occurs during the aging process. The Tidball lab uses proteomic approaches to identify specific, key substrates in proteolytic cascades that lead to muscle wasting. Subsequent experimentation relies on genetic manipulations designed to disrupt the cascades, with the goal of reducing sarcopenia. Identification of the mechanisms through which pro-inflammatory, Th1 cytokines can modulate muscle wasting during aging by influencing the state of activation proteases that drive muscle wasting is also major component of the sarcopenia investigations in the Tidball lab.
- Foster W.H., Tidball J.G., Wang Y., “p38γ activity is required for maintenance of slow skeletal muscle size,” Muscle Nerve. 2012 Feb;45(2):266-73.
- Villalta S.A., Deng B., Rinaldi C., Wehling-Henricks M., Tidball J.G., “IFN-γ 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 Nov 15;187(1):5419-28. Epub 2011 Oct 17.
- Wehling-Henricks M., Tidball J.G., “Neuronal nitric oxide synthase-rescue of dystrophin/utrophin double knockout mice does not require nNOS localization to the cell membrane,” PLoS One. 2011;6(10):e25071. Epub 2011 Oct 7.
- Villalta S.A., Rinaldi C., Deng B., Liu G., Fedor B., Tidball J.G., “Interleukin-10 reduces the pathology of mdx muscular dystrophy by deactivating M1 macrophages and modulating macrophage phenotype,” Hum Mol Genet. 2011 Feb 15;20(4):790-805. Epub 2010 Nov 30.
- Wehling-Henricks M., Jordan M.C., Gotoh T., Grody W.W., Roos K.P., Tidball J.G., “Arginine metabolism by macrophages promotes cardiac and muscle fibrosis in mdx muscular dystrophy,” PLoS One. 2010 May 21;5(5):e10763.
- Tidball J.G., Villalta S.A., “Regulatory interactions between muscle and the immune system during muscle regeneration,” Am J Physiol REgul Integr Comp Physiol. 2010 May;298(5):R1173-87. Epub 2010 mar 10. Review.
- Wehling-Henricks M., Oltmann M., Rinaldi C., Myung K.H., Tidball J.G., “Loss of positive allosteric interactions between neuronal nitric oxide synthase and phosphofructokinase contributes to defects in glycolysis and increased fatigability in muscular dystrophy,” Hum Mol Genet. 2009 Sep 15;19(18):3439-51. Epub 2009 Jun 19.
- Deng B., Glanzman D., Tidball J.G., “Nitric oxide generated by muscle corrects defects in hippocampal neurogenesis and neural differentiation caused by muscular dystrophy,” J Physiol. 2009 Apr 15;578(Pt 8):1769-78. Epub 2009 Feb 23.
- Villalta S.A., Nguyen H.X., Deng B., Gotoh T. Tidball J.G., “Shifts in macrophage phenotypes and macrophage competition for arginine metabolism affect the severity of muscle pathology in muscular dystrophy,” Hum Mol Genet. 209 Feb 1;18(3):482-96. Epub 2008 Nov 7.
- Wehling-Henricks M., Sokolow S. Lee J.J., Myung K.H., Villalta S.A., Tidball J.G., “Major basic protein-1 promotes fibrosis of dystrophic muscle and attenuates the cellular immune response in muscular dystrophy,” Hum Mol Genet. 20088 Aug 1;17(15):2280-92. Epub 2009 Apr 21.