Enhancement of skeletal muscle growth and repair is a central therapeutic target for the muscular dystrophies, sarcopenia, and muscle rehabilitation after disuse or acute injury. Insulin-like growth factor I (IGF-I) has long been recognized as one of the critical factors for promoting muscle growth and enhancing muscle regeneration through its regulation of protein synthesis and of satellite cell actions. 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. Satellite cells are normally quiescent unless triggered by signals such as IGF-I that are increased during muscle growth or after damage. In addition to IGF-I, a newly identified partner in the resolution of muscle damage is matrix-metalloproteinase 13 (MMP-13). We have found that increased IGF-I production by skeletal muscle also drives MMP-13 expression, and so these proteins may complement each other in the repair process. The current status of IGF-I therapeutics is founded on systemic delivery of recombinant IGF-I. However, because IGF-I is a potent growth factor in many tissues of the body and poses a potential carcinogenic risk, investigators have introduced IGF-I in limiting amounts. Thus, clinical trials have produced mixed results because the ability for IGF-I to provide any benefit to skeletal muscle is constrained by both the low level of protein administered, as well as the limited distribution of IGF-I to the muscle by the circulation. In our earlier work (Barton-Davis, et al 1998;Barton et al, 2002;Barton, 2006), this was circumvented by gene delivery allowing expression of IGF-I under a muscle-specific promoter. We now seek to define in a large animal model (dog), the optimal IGF-I related therapeutic for delivery in a viral (AAV) vector). We also seek to recapitulate this specificity viral gene expression with a small molecule therapeutic. Differential screens were set up to find compounds that can modulate IGF-I levels in skeletal muscle cells, but not in hepatocytes. Such molecules have been identified by working closely with a small New Jersey biotech company (PTC Therapeutics) that has developed proprietary technology to screen for small molecules that can selectively modulate translation of target mRNA (screens involve targeting the 5'and 3'UTRs).
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. Development of new agents that can enhance muscle regeneration, and evaluation of these agents in animal models is a critical step for translation to the clinic.
|Smith, Lucas R; Barton, Elisabeth R (2018) Regulation of fibrosis in muscular dystrophy. Matrix Biol 68-69:602-615|
|Smith, Lucas R; Hammers, David W; Sweeney, H Lee et al. (2016) Increased collagen cross-linking is a signature of dystrophin-deficient muscle. Muscle Nerve 54:71-8|
|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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