The 71 integrin is increased in skeletal muscle in response to injury-producing exercise and transgenic overexpression of this integrin in mice protects against exercise-induced muscle damage. This study investigates whether the increase in the 71 integrin observed in wild type mice in response to exercise is due to transcriptional regulation and examines whether mobilization of the integrin at the myotendinous junction (MTJ) is a key determinant in its protection against damage. A single bout of downhill running exercise selectively increased transcription of the 7 integrin gene in 5 wk-old wild type mice 3 h postexercise and increased 7 chain was detected in muscle sarcolemma adjacent to tendinous tissue immediately following exercise. The 7B, but not 7A isoform, was found concentrated and co-localized with tenascin-C in muscle fibers lining the MTJ. To further validate the importance of the integrin in the protection against muscle damage following exercise, muscle injury was quantified in 7^-/- mice. Muscle damage was extensive in 7^-/- mice in response to both a single and repeated bouts of exercise and was largely restricted to areas of high MTJ concentration and high mechanical force near the Achilles tendon. These results suggest that exercise-induced muscle injury selectively increases transcription of the 7 integrin gene and promotes a rapid change in the 71 integrin at the myotendinous junction. These combined molecular and cellular alterations are likely responsible for integrin-mediated attenuation of exercise-induced muscle damage.