PAI-1, the Plasminogen System, and Skeletal Muscle

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.

Keywords: aging; diabetes; exercise; muscular dystrophy; pathophysiology; plasminogen activator inhibitor-1; plasminogen system; regeneration; skeletal muscle; therapeutics.

Figure 1

Illustration of plasminogen activator inhibitor-1 (PAI-1) linear (A) and crystalline (B) structure. Crystalline structure adapted from [101,102].

Figure 2

Serpine1 transcriptional regulation and PAI-1 function. Serpine1 can be transcribed through several signaling cascades including pro-fibrogenic (A), pro-inflammatory (B), and pro-growth/hormonal signaling cascades (C). Once transcribed, PAI-1 is secreted in its active form into the extracellular space where it can inhibit urokinase-type PA (uPA)/tissue-type PA (tPA), and thus inhibit downstream extracellular matrix (ECM) degradation by preventing matrix metalloproteinase (MMP) activation (D,E). Conversely, PAI-1 may be rapidly converted to its more stable latent state. The active and latent PAI-1 molecules can interact with uPA/uPA receptor (uPAR) and integrins to diminish cell adhesion to vitronectin (F). Vitronectin-bound PAI-1 prevents its premature conversion to its latent state and improves its binding affinity to uPA/tPA. PAI-1 may also be internalized by the cell, through its interaction with lipoprotein receptor-related protein 1 (LRP1) and uPA/uPAR, ultimately leading to its degradation or recycling (G). Solid black arrows indicate activation. Dotted black lines indicate potential yet unfavorable pathways. Red bars indicate inhibition or blockage. Two-way arrows indicate interaction between proteins.

Figure 3

Effects of PAI-1 during skeletal muscle regeneration. Induction of muscle damage results in the swift infiltration of immune cells (macrophages shown), resulting in the degradation of cellular debris and activation of satellite cells to form myoblasts. The activated myoblasts differentiate and fuse to form myotubes, which then mature within their niche to form complete myofibres. PAI-1 has been shown to inhibit the regeneration process at various levels (red bar lines), however the role of PAI-1 relating to satellite cell, myoblast and other cells (immune and fibrogenic cells) during regeneration has yet to be explored. Solid black arrows indicate activation. Red bars indicate inhibition or blockage.

Figure 4

PAI-1 in muscle pathology and therapeutics. Excessive PAI-1 levels lead to increased fibrosis and are associated with inflammation. In skeletal muscle, this results in impaired regeneration and reduced muscle mass in various pathological states. Exercise and pharmacological agents reduce circulating PAI-1 levels and serve as a therapeutic approach to normalize PAI-1 levels and improve skeletal muscle health.