Skeletal muscle repair is a central therapeutic target for the muscular dystrophies, sarcopenia, and muscle rehabilitation after disuse or acute injury. Because muscle fibers are post-mitotic, repair must rely on satellite cells, a stem cell-like population residing close to muscle fibers as a source for replenishing nuclear content of the muscle. The ability and efficiency of satellite cell proliferation, differentiation, migration, and fusion to sites of injury are all important steps in the resolution of damage. IGF-I has long been recognized as one of the critical factors for regulating satellite cell actions during muscle regeneration, helping to repair damaged regions of the fibers, and to promote muscle growth. There is now a growing interest in the characterization of additional potentially active peptides produced by the igf1 gene. Alternative splicing of the gene results in multiple isoforms that retain the identical sequence for mature IGF-I, but also give rise to divergent C-terminal sequences, called the E-peptides. Recent evidence from our lab demonstrates that the E- peptide extensions directly regulate critical steps in muscle repair. First, the rodent EA and EB peptides stimulate proliferation of muscle cells in culture, potentially increasing the number of satellite cell available for repair. Second, the EA-peptide enhances expression and secretion of IGF-I during differentiation. Third, the EB-peptide regulates expression of matrix metalloproteinases, specifically MMP-13 in an IGF-I independent manner. In other tissue types, MMP-13 activity is a key regulator of wound healing, bone remodeling, and tumor invasion, as well as a modulator of additional MMP activity. Therefore, MMP-13 may improve muscle repair by enhancing satellite cell migration through the extracellular matrix, and by coordinating matrix remodeling around newly formed muscle fibers. Preliminary measurements of MMP-13 expression during muscle regeneration show that it is elevated during later stages of repair after fibers have begun to form. Further, MMP-13 expression is higher in muscles from the mdx mouse, where the absence of dystrophin leads to increased cycles of degeneration and regeneration. These studies suggest that MMP-13 is important component of muscle repair. The goals of this grant are (1) to determine if MMP-13 can accelerate proper resolution of muscle damage associated with genetic disease and after acute injury, and (2) to understand the functional links between IGF- I, the E peptides and MMP-13 activity. The mechanisms underlying their actions are essential to understand so that repair-enhancing therapies based on their functions can be developed.

Public Health Relevance

Skeletal muscle repair occurs after acute injury and is an ongoing symptom associated with genetic muscle disease, specifically in the muscular dystrophies. Therefore, the therapies that enhance muscle regeneration can benefit patients suffering from genetic disease, those recovering from muscle injury, and the elderly. Understanding the mechanisms underlying muscle regeneration is of primary importance so that new agents can be developed to aid in the repair process.

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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Nuckolls, Glen H
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University of Pennsylvania
Anatomy/Cell Biology
Schools of Medicine
United States
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Smith, Lucas R; Barton, Elisabeth R (2018) Regulation of fibrosis in muscular dystrophy. Matrix Biol 68-69:602-615
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Bikle, Daniel D; Tahimic, Candice; Chang, Wenhan et al. (2015) Role of IGF-I signaling in muscle bone interactions. Bone 80:79-88
Durzy?ska, Julia; Barton, Elisabeth (2014) IGF expression in HPV-related and HPV-unrelated human cancer cells. Oncol Rep 32:893-900
Brisson, Becky K; Spinazzola, Janelle; Park, SooHyun et al. (2014) Viral expression of insulin-like growth factor I E-peptides increases skeletal muscle mass but at the expense of strength. Am J Physiol Endocrinol Metab 306:E965-74
Smith, Lucas R; Barton, Elisabeth R (2014) SMASH - semi-automatic muscle analysis using segmentation of histology: a MATLAB application. Skelet Muscle 4:21
Philippou, Anastassios; Barton, Elisabeth R (2014) Optimizing IGF-I for skeletal muscle therapeutics. Growth Horm IGF Res 24:157-63
Smith, Lucas R; Barton, Elisabeth R (2014) Collagen content does not alter the passive mechanical properties of fibrotic skeletal muscle in mdx mice. Am J Physiol Cell Physiol 306:C889-98
Park, Soohyun; Brisson, Becky K; Liu, Min et al. (2014) Mature IGF-I excels in promoting functional muscle recovery from disuse atrophy compared with pro-IGF-IA. J Appl Physiol (1985) 116:797-806
Durzynska, Julia; Philippou, Anastassios; Brisson, Becky K et al. (2013) The pro-forms of insulin-like growth factor I (IGF-I) are predominant in skeletal muscle and alter IGF-I receptor activation. Endocrinology 154:1215-24

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