Degeneration of dystrophic or injured skeletal muscles induces high expression of Galectin-1

Abstract

Muscle degenerative diseases such as Duchenne Muscular Dystrophy are incurable and treatment options are still restrained. Understanding the mechanisms and factors responsible for muscle degeneration and regeneration will facilitate the development of novel therapeutics. Several recent studies have demonstrated that Galectin-1 (Gal-1), a carbohydrate-binding protein, induces myoblast differentiation and fusion in vitro, suggesting a potential role for this mammalian lectin in muscle regenerative processes in vivo. However, the expression and localization of Gal-1 in vivo during muscle injury and repair are unclear. We report the expression and localization of Gal-1 during degenerative-regenerative processes in vivo using two models of muscular dystrophy and muscle injury. Gal-1 expression increased significantly during muscle degeneration in the murine mdx and in the canine Golden Retriever Muscular Dystrophy animal models. Compulsory exercise of mdx mouse, which intensifies degeneration, also resulted in sustained Gal-1 levels. Furthermore, muscle injury of wild-type C57BL/6 mice, induced by BaCl(2) treatment, also resulted in a marked increase in Gal-1 levels. Increased Gal-1 levels appeared to localize both inside and outside the muscle fibers with significant extracellular Gal-1 colocalized with infiltrating CD45(+) leukocytes. By contrast, regenerating muscle tissue showed a marked decrease in Gal-1 to baseline levels. These results demonstrate significant regulation of Gal-1 expression in vivo and suggest a potential role for Gal-1 in muscle homeostasis and repair.

Ligand Reduces Galectin-1 Sensitivity to Oxidative Inactivation by Enhancing Dimer Formation

“…As a result, cellular movement into different redox environments may actually facilitate Gal-1 oxidation and therefore allow cells initially targeted for phagocytic removal to become re-engaged in host defense following PS reversion. In contrast, leukocyte-mediated damage of viable tissue may facilitate the release of reduced Gal-1 from intracellular stores that then engage leukocytes and induce their turnover (6,55).…”

Evolving Mechanistic Insights into Galectin Functions

“…In addition to epithelial repair, early studies suggested that Gal-1 might facilitate muscle development and repair by inducing myotube fusion and fibroblast to myocyte transdifferentiation [124, 125]. Gal-1 displays a unique striated localization pattern within muscle and muscle injury results in a significant increase in Gal-1 expression [126, 127]. Gal-1 KO mice exhibit impaired muscle regeneration following BaCl 2 -induced muscle injury [124].…”

“…Rapid oxidation of Gal-1 following tissue damage likely reduces the ability of Gal-1 and other galectins to inhibit neutrophils and other leukocytes immediately following injury, allowing these cells to neutralize potential pathogens and remove necrotic debris. However, as neutrophils and other leukocytes encroach on viable tissue surrounding an area of inflammation, leukocyte mediated-damage may release reduced, and therefore active, Gal-1, allowing engagement of leukocyte ligands and signaling of leukocyte turnover [127, 188]. Furthermore, while the redox environment can directly impact Gal-1 function, several studies suggest that the redox status of the cells themselves may also alter cellular sensitivity to Gal-1 signaling.…”

Detection of Phosphatidylserine Exposure on Leukocytes Following Treatment with Human Galectins

“…However, as neutrophils begin to encroach on viable tissue following the removal of necrotic debris, release of reduced, and therefore active, galectin likely results in galectin engagement and induction of preaparesis in neutrophils, thereby facilitating macrophage-mediated removal (Fig. 1) [9, 20, 21]. In contrast, as T cells often do not accumulate at the same rate or magnitude as neutrophils and also display a targeted approach to their activity [22, 23], apoptotic cell death is likely sufficient to induce cellular removal without causing deleterious consequences in the setting of inflammation.…”