Muscle fibrosis is a prominent pathological feature of chronic muscle diseases, including muscular dystrophies. It directly leads to muscle dysfunction and clinical muscle weakness. Duchenne muscular dystrophy (DMD) is the most common genetic muscle disease with no cure at this point. Previous studies by our lab and others have demonstrated that ameliorating muscle fibrosis represents a viable therapeutic approach to improve muscular dystrophy phenotype in mdx mice, a mouse model for DMD. Fibrosis is caused by excessive deposition of extracellular matrix (ECM) proteins, which are primarily produced by tissue effector fibroblasts. Extensive research in fibrotic disease models of non-muscle tissues has shown that the circulation-derived fibrocyte is an important cellular mediator of tissue fibrogenesis by producing ECM proteins and profibrotic cytokines as well as differentiating into tissue effector fibroblasts. The chemokine system is essential to the recruitment and fibrogenic functions of fibrocytes. Our preliminary study showed that fibrocytes were also present in a DMD patient muscle biopsy and in mdx diaphragm, the only skeletal muscle in mdx mice that undergoes progressive fibrosis. We further showed that mdx diaphragm fibrocytes expressed chemokine receptors CCR1, CCR2, CCR5, and CXCR4. This study is to address our central hypothesis that fibrocytes play a pathogenic role in skeletal muscle fibrogenesis associated with DMD, the chemokines and chemokine receptors are involved in skeletal muscle recruitment and fibrogenic functions of fibrocytes, and blocking relevant chemokine receptors and their ligands can inhibit fibrocyte recruitment and fibrogenic functions and ameliorate fibrosis in dystrophic muscles. We will address our hypothesis through three Specific Aims.
Specific Aim 1 will characterize muscle recruitment and effector properties of mdx diaphragm fibrocytes.
Specific Aim 2 will characterize the chemokine receptors and ligands involved in mdx diaphragm fibrocyte recruitment and fibrogenic functions.
Specific Aim 3 will test therapeutic interventions to inhibit chemokine receptors and ligands identified in Aim 2 to establish novel therapeutic targets for DMD. Our long-term goal is to utilize the knowledge gained from these studies to develop novel antifibrotic therapies for DMD.

Public Health Relevance

Project Narrative: Duchenne muscular dystrophy (DMD) is the most common and lethal muscle disease with no cure at this point. Scar formation is evident and progressive in muscles of DMD patients. It causes muscle dysfunction and weakness. Fibrocytes are cells that have been shown to contribute to scar formation in the disease mouse models of lung, kidney, and liver. We have found that fibrocytes were present in muscle biopsy tissue of a DMD patient and in the muscle which undergoes progressive scar formation in mdx mice, a mouse model for DMD. We thus propose this study to characterize the functions of muscle fibrocytes and their contribution to muscle scar formation in mdx mice. We will also determine which chemokines and chemokine receptors regulate muscle fibrocyte functions, and test whether inhibit these regulatory proteins can suppress fibrocyte functions and reduce muscle scar formation. Our long-term goal is to utilize the knowledge gained from these studies to develop novel therapies to reduce scar formation and improve muscle function for patients with DMD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR059702-03
Application #
8250338
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Nuckolls, Glen H
Project Start
2011-04-01
Project End
2016-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
3
Fiscal Year
2012
Total Cost
$381,375
Indirect Cost
$156,375
Name
Icahn School of Medicine at Mount Sinai
Department
Neurology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029