Abstract
The plasminogen system is a critical proteolytic system responsible for the remodeling of the extracellular matrix (ECM). The master regulator of the plasminogen system, plasminogen activator inhibitor-1 (PAI-1), has been implicated for its role in exacerbating various disease states not only through the accumulation of ECM (i.e., fibrosis) but also its role in altering cell fate/behaviour. Examination of PAI-1 has extended through various tissues and cell-types with recent investigations showing its presence in skeletal muscle. In skeletal muscle, the role of this protein has been implicated throughout the regeneration process, and in skeletal muscle pathologies (muscular dystrophy, diabetes, and aging-driven pathology). Needless to say, the complete function of this protein in skeletal muscle has yet to be fully elucidated. Given the importance of skeletal muscle in maintaining overall health and quality of life, it is critical to understand the alterations—particularly in PAI-1—that occur to negatively impact this organ. Thus, we provide a comprehensive review of the importance of PAI-1 in skeletal muscle health and function. We aim to shed light on the relevance of this protein in skeletal muscle and propose potential therapeutic approaches to aid in the maintenance of skeletal muscle health.
Highlights
The plasminogen system is a proteolytic system responsible for the degradation of several proteins, most notably, fibrin
This review will summarize the biology of plasminogen activator inhibitor-1 (PAI-1) and the plasminogen system as it relates to overall tissue function and extracellular matrix (ECM) remodeling, highlight the role of PAI-1 in skeletal muscle, and shed light on potential therapeutic strategies to reduce or normalize PAI-1 levels in an attempt to improve muscle and overall health
Serpine1 KO animals were found to have elevated macrophage numbers from 3 days to 5 days post-CTX [28]. Together these data suggest that unbound/soluble urokinase-type PA (uPA) activity is needed for muscle regeneration, and PAI-1 can negatively impact its role in regeneration
Summary
The plasminogen system is a proteolytic system responsible for the degradation of several proteins, most notably, fibrin. Plasminogen is activated by plasminogen activators (PAs): tissue-type PA (tPA) and urokinase-type PA (uPA) It was not until the 1980s when the major regulator of the plasminogen system, plasminogen activator inhibitor-1 (PAI-1), was identified [8,9]. PAI-1 plays critical roles in response to skeletal muscle injury and in myopathic conditions [27,28,29,34,35], further highlighting the importance of the plasminogen system and ECM remodeling to skeletal muscle. This review will summarize the biology of PAI-1 and the plasminogen system as it relates to overall tissue function and ECM remodeling, highlight the role of PAI-1 in skeletal muscle, and shed light on potential therapeutic strategies to reduce or normalize PAI-1 levels in an attempt to improve muscle and overall health
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