High mechanical loading was hypothesized to induce the expression of angiogenic and/or lymphangiogenic extracellular matrix (ECM) proteins in skeletal muscle. Eight men performed a strenuous exercise protocol, which consisted of 100 unilateral maximal drop jumps followed by submaximal jumping until exhaustion. Muscle biopsies were taken 30 min and 48 h post exercise from the vastus lateralis muscle and analyzed for the following parameters: mRNA and protein expression of ECM-associated CCN proteins (Cyr61/CCN1, CTGF/CCN2), and mRNA expression of vascular endothelial growth factors (VEGFs) and Hif-1. The mRNA expression of Cyr61 and CTGF increased 30 min after the exercise (14- and 2.5-fold, respectively, P< 0.001). Cyr61 remained elevated 48 h post exercise (3-fold, P < 0.05). The mRNA levels of VEGF-A, VEGF-B, VEGF-C, VEGF-D or Hif-1 did not change significantly at either 30 min or 48 h post exercise; however, the variation between subjects increased markedly in VEGF-A and VEGF-B mRNA. Cyr61 protein levels were higher at both 30 min and 48 h after the exercise compared to the control (P < 0.05). Cyr61 and CTGF proteins were localized to muscle fibers and the surrounding ECM by immunohistochemistry. Fast fibers stained more intensively than slow fibers. In conclusion, mechanical loading induces rapid expression of CCN proteins in human skeletal muscle. This may be one of the early mechanisms involved in skeletal muscle remodeling after exercise, as Cyr61 and CTGF regulate the expression of genes involved in angiogenesis and ECM remodeling.