The maintenance of muscle tissue declines with age, leading to both loss of muscle mass and strength, as well as impaired regeneration following injury. One of the more important aspects of this aspect of aging appears to be loss of function in muscle stem cell populations, but a broad selection of other contributing mechanisms have been identified over the years. Here, researchers dig into the biochemistry of muscle regeneration in order to identify more specific areas of dysfunction. This sort of work tends to identify changed levels of protein expression, a proximate cause of the problem at hand, but in most cases it remains a struggle to link regulatory changes in important processes with specific deeper causes of aging.
Skeletal muscle constitutes approximately 40% of the total mass of the human body and plays a central role in health and well-being. 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. 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. Each stage is essential to drive the following subsequent stage, thereby imparting coherence to the overall regeneration process.
The extracellular matrix (ECM) is critical in maintaining normal skeletal muscle function and driving skeletal muscle regeneration. Skeletal muscle ECM is composed of a plethora of structural, adhesion, and signal-stimulating proteins that are transiently degraded and reconstituted depending on the mode and severity of tissue injury. Aged skeletal muscle does not regenerate well in response to injury, and there is evidence of impairment at each stage of the regeneration process including accumulation of collagen (i.e., fibrosis). However, it is unclear if this age-related skeletal muscle fibrosis occurs as a result of impaired degradation in the first week following tissue damage.
We investigated ECM proteins and their regulators during early regeneration timepoints. 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. 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.