Impaired ECM Remodeling and Macrophage Activity Define Necrosis and Regeneration Following Damage in Aged Skeletal Muscle

• Published in: International journal of molecular sciences Vol. 21; no. 13; p. 4575
• Main Authors: Rahman, Fasih Ahmad, Angus, Sarah Anne, Stokes, Kyle, Karpowicz, Phillip, Krause, Matthew Paul
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 27.06.2020; MDPI
• Subjects: Age; aging; Animals; Collagen; Collagen (type I); Extracellular matrix; Extracellular Matrix - metabolism; Extracellular Matrix - pathology; Extracellular Matrix Proteins - metabolism; Gelatinase B; Inhibitors; macrophage; Macrophage Activation; Macrophages; Macrophages - metabolism; Macrophages - pathology; Male; Matrix metalloproteinase; Matrix metalloproteinases; Metalloproteinase; Mice; Mice, Inbred C57BL; Muscle, Skeletal - cytology; Muscle, Skeletal - injuries; Muscle, Skeletal - metabolism; Muscles; Musculoskeletal system; Necrosis; plasminogen activator inhibitor-1; Plasminogen activator inhibitors; Proteins; Regeneration; Regulators; Skeletal muscle; Tibialis anterior muscle; macrophage; plasminogen activator inhibitor-1; aging; skeletal muscle; regeneration; extracellular matrix
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21134575

Regenerative capacity of skeletal muscle declines with age, the cause of which remains largely unknown. We investigated extracellular matrix (ECM) proteins and their regulators during early regeneration timepoints to define a link between aberrant ECM remodeling, and impaired aged muscle regeneration. The regeneration process was compared in young (three month old) and aged (18 month old) C56BL/6J mice at 3, 5, and 7 days following cardiotoxin-induced damage to the tibialis anterior muscle. Immunohistochemical analyses were performed to assess regenerative capacity, ECM remodeling, and the macrophage response in relation to plasminogen activator inhibitor-1 (PAI-1), matrix metalloproteinase-9 (MMP-9), and ECM protein expression. The regeneration process was impaired in aged muscle. Greater intracellular and extramyocellular PAI-1 expression was found in aged muscle. Collagen I was found to accumulate in necrotic regions, while macrophage infiltration was delayed in regenerating regions of aged muscle. Young muscle expressed higher levels of MMP-9 early in the regeneration process that primarily colocalized with macrophages, but this expression was reduced in aged muscle. Our results indicate that ECM remodeling is impaired at early time points following muscle damage, likely a result of elevated expression of the major inhibitor of ECM breakdown, PAI-1, and consequent suppression of the macrophage, MMP-9, and myogenic responses.