Abstract
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.
Highlights
Skeletal muscle constitutes approximately 40% of the total mass of the human body and plays a central role in health and well-being [1]
To investigate the acute regenerative capacity of aged skeletal muscle, we first induced damaged to the left tibialis anterior (TA) muscle via cardiotoxin (CTX) injection and analyzed samples after 3, 5, and 7 days
The findings presented here demonstrate that several aspects of the regeneration process are impaired in aged skeletal muscle in the first week following skeletal muscle damage
Summary
Skeletal muscle constitutes approximately 40% of the total mass of the human body and plays a central role in health and well-being [1]. A combination of neurodegeneration, an altered hormonal and metabolic profile, and reduced regenerative capacity leads to a deterioration of skeletal muscle culminating in loss of muscle mass, quality, and function. Central to the maintenance of a healthy skeletal muscle mass is its regenerative capacity, enabling muscle to completely restore function within 7–10 days after severe damage [7]. The regeneration process can be categorized into the following three sequential but widely overlapping stages: (1) inflammation and necrosis of damaged myofibres, (2) activation, proliferation, differentiation, and fusion of satellite cells, and (3) maturation and remodeling of the regenerated muscle [7,8,9,10]. Each stage is essential to drive the following subsequent stage, thereby imparting coherence to the overall regeneration process
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