Skeletal muscle injury resulting from occupational and physical activities, trauma, and disease elicits an inflammatory response within the affected muscle. The local inflammatory response, consisting of adhesion molecules, myeloid cells, and cytokines, is critically important in restoring structure and function to injured muscle as it regulates cellular and molecular events of myogenesis. Mechanisms through which the inflammatory response facilitates myogenesis are not well understood. We have begun to establish a novel mechanism through which the inflammatory response facilitates myogenesis by demonstrating that intercellular adhesion molecule-1 (ICAM-1), an important adhesion molecule of the inflammatory response, contributes to regenerative and hypertrophic processes in skeletal muscle after mechanical loading (1). To test the specific contribution of skeletal muscle cell expression of ICAM-1 to regenerative and hypertrophic processes, we genetically engineered myoblasts to stably express ICAM-1. Preliminary studies found that the expression of ICAM-1 by cultured skeletal muscle cells augmented stages of myogenesis in which myotubes are forming, adding nuclei, aligning, synthesizing proteins, and hypertrophying. The objective of the proposed research is to elucidate mechanisms through which ICAM-1 augments regenerative and hypertrophic processes associated with restoring structure and function to injured muscle. This objective will be achieved using genetic, biochemical, and pharmacological approaches, as well as established models and assays of myogenesis.
Aim 1, using myoblasts that have been genetically engineered to express full length ICAM-1, the extracellular domain of ICAM-1, or the cytoplasmic domain of ICAM-1, will identify mechanisms through which ICAM-1 expression augments stages of in vitro myogenesis. We hypothesize that the adhesive function of the extracellular domain of ICAM-1 augments adhesion and subsequent fusion of myoblasts through mechanisms involving homophilic interactions and remodeling of the actin cytoskeleton. We also hypothesize that the signal transducing function of the cytoplasmic domain of ICAM-1 augments myoblast fusion, as well as myotube alignment, protein synthesis, and size by activating intracellular signaling pathways (Rho GTPases and mTOR) that regulate distinct stages of myogenesis.
Aim 2 will test the hypothesis that ICAM-1 is expressed by satellite cells/myoblasts and regenerating myofibers in injured muscle, and that their expression of ICAM-1 contributes to the restoration of structure and function to injured muscle. This hypothesis will be tested by exposing muscles of wild type and ICAM-1-/- mice to a muscle injury protocol and assaying for ICAM-1 localization, satellite cells/myoblasts, regenerating myofibers, myeloid cells, and muscle function. The proposed research will yield novel information on mechanisms through which ICAM-1 augments myogenesis and the relevance of such mechanisms to restoring structure and function to injured muscle. This information will accelerate the development of new approaches for rehabilitating musculoskeletal injuries and promoting skeletal muscle growth, particularly in older individuals.
Musculoskeletal injuries are difficult to rehabilitate because of a poor understanding of how the inflammatory response, which is a normal response to injury, helps restore structure and function to injured muscle. The proposed studies will provide novel information on how an important protein of the inflammatory response, known as intercellular adhesion molecule-1, facilitates the restoration of structure and function to injured muscle.
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|Dearth, Christopher L; Goh, Qingnian; Marino, Joseph S et al. (2013) Skeletal muscle cells express ICAM-1 after muscle overload and ICAM-1 contributes to the ensuing hypertrophic response. PLoS One 8:e58486|