Much emphasis has been placed on the description of age-related changes in skeletal muscle physiology. The present paper summarizes the chemical characterization of age-related post-translational modifications of the rat skeletal muscle sarcoplasmic reticulum (SR) Ca-ATPase isoforms SERCA1 and SERCA2a obtained from 5- and 28-month-old male Fischer 344 rats. Whereas the SERCA1 isoform shows an age-dependent loss of Cys and Arg, the SERCA2a isoform displays a loss of Cys but also a significant accumulation of 3-nitrotyrosine. The in vitro exposure of SR vesicles particularly rich in SERCA1 (>90%) from 5-month-old rats to low levels of peroxyl radicals yielded SR vesicles with physical properties of the SR Ca-ATPase identical to those observed for the SR Ca-ATPase obtained from 28-month-old rats. The peroxyl radical-modified SR Ca-ATPase showed a loss of Cys and Arg but also of Ser and Met, indicating that peroxyl radicals, though a good model oxidant to generate 'aged' SR vesicles, may not be the only oxidant responsible for the chemical modification of the SR Ca-ATPase in vivo. In fact, efficient thiol modification of the SERCA1 was also observed after the exposure to peroxynitrite. Peroxynitrite selectively nitrated the tyrosine residues of the SERCA2a isoform even in the presence of an excess of SERCA1. Thus, peroxynitrite may be responsible for the age-dependent modification of the SR Ca-ATPase in vivo.