A goal of our research is to understand mechanisms through which the immune system influences the pathology of Duchenne muscular dystrophy (DMD). As our understanding of the immunobiology of muscular dystrophy has advanced, clear evidence shows that the immune response to dystrophic muscle promotes muscle damage, at least in some stages of the disease. That knowledge has led to the expectation that suppressing the immune response can reduce the rate of progress or severity of the disease. However, a potential danger of using non-specific immunosuppressants to treat muscular dystrophy exists. The immune system can also promote tissue repair so that the broad application of immunosuppression as a treatment may have a net, negative effect on muscle health. Thus, a critical barrier to developing immune-based treatments for muscular dystrophy is the shortage of mechanistic knowledge of the diverse, complex and dynamic interactions between dystrophic muscle and the immune system. The focus of our study will be to determine the role of immune cells in the myeloid lineage for regulating muscle regeneration and test the novel hypothesis that myeloid cell production of the protein Klotho drives regeneration. We will pursue the following aims, using the mdx mouse model of DMD:
Aim 1. Test the hypothesis that a protein expressed by M2 macrophages, called Klotho, promotes regeneration of dystrophic muscle.
Aim 2. Test the hypothesis that Klotho modulates muscle inflammation in dystrophic mice.
Aim 3. Test the hypothesis that increased expression of Klotho reduces pathology in severe muscular dystrophy caused by mutation of both dystrophin and utrophin. Collectively, these findings will provide new understandings concerning the role of macrophages in the regeneration of dystrophic muscle. We anticipate that this information can provide the foundation for future work in which the pro-regenerative influences of the immune system on dystrophic muscle can be exploited to reduce the pathology of DMD.

Public Health Relevance

Duchenne muscular dystrophy is a progressive, lethal, muscle wasting disease with no cure. Our investigation will examine the role of the immune system in regulating the pathology of muscular dystrophy, with an emphasis on elucidating mechanisms through which the immune system can promote muscle regeneration.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Skeletal Muscle and Exercise Physiology Study Section (SMEP)
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Cheever, Thomas
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University of California Los Angeles
Schools of Arts and Sciences
Los Angeles
United States
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Wehling-Henricks, Michelle; Welc, Steven S; Samengo, Guiseppina et al. (2018) 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. Hum Mol Genet 27:14-29
Tidball, James G (2017) Regulation of muscle growth and regeneration by the immune system. Nat Rev Immunol 17:165-178
Chadwick, Jessica A; Swager, Sarah A; Lowe, Jeovanna et al. (2016) Myeloid cells are capable of synthesizing aldosterone to exacerbate damage in muscular dystrophy. Hum Mol Genet 25:5167-5177
Wehling-Henricks, Michelle; Li, Zhenzhi; Lindsey, Catherine et al. (2016) Klotho gene silencing promotes pathology in the mdx mouse model of Duchenne muscular dystrophy. Hum Mol Genet 25:2465-2482
Tidball, James G; Wehling-Henricks, Michelle (2015) Shifts in macrophage cytokine production drive muscle fibrosis. Nat Med 21:665-6
Tidball, James G; Welc, Steven S (2015) Macrophage-Derived IGF-1 Is a Potent Coordinator of Myogenesis and Inflammation in Regenerating Muscle. Mol Ther 23:1134-1135
Tidball, James G; Wehling-Henricks, Michelle (2014) Nitric oxide synthase deficiency and the pathophysiology of muscular dystrophy. J Physiol 592:4627-38
Tidball, James G; Bertoni, Carmen (2014) Purloined mechanisms of bacterial immunity can cure muscular dystrophy. Cell Metab 20:927-9
Villalta, S Armando; Rosenthal, Wendy; Martinez, Leonel et al. (2014) Regulatory T cells suppress muscle inflammation and injury in muscular dystrophy. Sci Transl Med 6:258ra142