Matrix Metalloproteinase Response to Acute Resistance Exercise is Altered in Osteoarthritic Adults with Increased Muscle Collagen and PDGFRα+ Mesenchymal Cells

Abstract

Background: Knee osteoarthritis (OA) is associated with knee extensor weakness, altered myofibre morphology, reduced satellite cell abundance and fibrillar muscle collagen accumulation in the vastus lateralis (VL). Fibrillar muscle collagen accumulation is associated with reduced knee extensor strength. Yet, its underlying mechanisms remain poorly understood. Satellite cells and PDGFR+ mesenchymal cells express collagen as well as proteins involved in collagen degradation and may be involved in muscle collagen accumulation. The present study assessed knee extensor function and myofibre morphology, satellite cells and PDGFR+ mesenchymal cells in adults with and without moderate-to-severe knee OA. It also investigated collagen remodeling by assessing how enzymes involved in collagen degradation (matrix metalloproteinases [MMPs]) respond to acute resistance exercise in the VL. This study aimed to better understand the cellular contributors to muscle collagen accumulation and knee extensor weakness in knee OA. Methods: Volunteers with and without moderate-to-severe knee OA had a resting muscle biopsy, then completed an acute bout of resistance exercise and had a 72-hour post-exercise biopsy. Knee extensor strength was measured on a Biodex dynamometer. In VL samples, MMP gene expression (qPCR), protein area fraction (immunofluorescence) and enzyme activity (zymography) were assessed. PDGFR+ mesenchymal cells, satellite cells, satellite cell-MMP9 colocalization and myofibre morphology were assessed by immunofluorescence. Fibrillar muscle collagen content was quantified by picrosirius red. Results: Participants with moderate-to-severe knee OA had weaker knee extensors (isometric and isokinetic), reduced muscle quality (isometric and isokinetic) and more fibrillar collagen than controls (12.2 {+/-} 4.8%, 8.4 {+/-} 2.9%, p = 0.006). Fibrillar collagen was negatively correlated with isokinetic concentric torque (r = -0.479, p = 0.006). Volunteers with knee OA had more PDGFR+ mesenchymal cells (p < 0.001) and fewer satellite cells than controls (p = 0.006). In both groups, resistance exercise upregulated MMP2 (p < 0.001), MMP9 (p = 0.001) and MMP14 (p < 0.001) gene expression as well as MMP2 (p < 0.001) and MMP9 (p = 0.001) enzyme activity. MMP2 and MMP9 protein area fraction increased in response to resistance exercise in controls, but this response was blunted in the knee OA group (age x time interaction, p = 0.041). Satellite cell-MMP9 colocalization fold change post-exercise was significantly different between groups (p = 0.048). Volunteers with knee OA had smaller myofibres (p < 0.001) and greater myofibre shape irregularity (p = 0.039), but no differences in thigh lean mass, capillary content or fibre-type distribution. Conclusions: Although exercise stimulated transcriptional and MMP activity responses in both groups, the ECM-specific protein response was impaired in knee OA. The findings suggest that dysregulated ECM remodeling facilitated by MMPs and alterations in PDGFR+ mesenchymal and satellite cell abundance may contribute to muscle collagen accumulation and knee extensor weakness in knee OA.