Dystrophin is a protein found on the cytoplasmic surface of skeletal muscle cell membranes. It is absent in patients with Duchenne muscular dystrophy (DMD) and in mdx mice, a model of X-linked muscular dystrophy. The study shows that dystrophin-deficient muscle fibers in mdx mice are more susceptible to sarcolemmal rupture during muscle contraction. The level of sarcolemmal damage is directly related to the mechanical stress during contraction, not the number of muscle activations. This suggests that dystrophin's primary function is to provide mechanical support to the sarcolemma, protecting it from stress during muscle contraction. The study used various contraction protocols to assess the effects of dystrophin deficiency. Eccentric contractions (ECC) caused the most damage, followed by isometric contractions (ISO) and repeated submaximal isometric contractions (ISO rep). Passive stretch (PAS) caused damage only in mdx mice. The relationship between peak force and the percentage of damaged fibers was significant, with mdx muscles showing greater damage. The slope of this relationship was steeper in mdx muscles, indicating a higher sensitivity to mechanical stress. The study also found that larger muscle fibers, such as those in the EDL muscle, showed more damage than smaller fibers in the diaphragm. This is consistent with the idea that larger fibers have a higher surface-to-volume ratio, leading to greater membrane stress. The findings suggest that dystrophin deficiency leads to increased membrane fragility and reduced regenerative capacity, contributing to muscle degeneration. The study's methodology could be useful in evaluating the effectiveness of dystrophin gene therapy in mdx mice. The results support the hypothesis that dystrophin's primary role is to reinforce the sarcolemma, protecting it from mechanical stress during muscle contraction. The study also highlights the importance of dystrophin in maintaining muscle integrity and the potential consequences of its deficiency in DMD.Dystrophin is a protein found on the cytoplasmic surface of skeletal muscle cell membranes. It is absent in patients with Duchenne muscular dystrophy (DMD) and in mdx mice, a model of X-linked muscular dystrophy. The study shows that dystrophin-deficient muscle fibers in mdx mice are more susceptible to sarcolemmal rupture during muscle contraction. The level of sarcolemmal damage is directly related to the mechanical stress during contraction, not the number of muscle activations. This suggests that dystrophin's primary function is to provide mechanical support to the sarcolemma, protecting it from stress during muscle contraction. The study used various contraction protocols to assess the effects of dystrophin deficiency. Eccentric contractions (ECC) caused the most damage, followed by isometric contractions (ISO) and repeated submaximal isometric contractions (ISO rep). Passive stretch (PAS) caused damage only in mdx mice. The relationship between peak force and the percentage of damaged fibers was significant, with mdx muscles showing greater damage. The slope of this relationship was steeper in mdx muscles, indicating a higher sensitivity to mechanical stress. The study also found that larger muscle fibers, such as those in the EDL muscle, showed more damage than smaller fibers in the diaphragm. This is consistent with the idea that larger fibers have a higher surface-to-volume ratio, leading to greater membrane stress. The findings suggest that dystrophin deficiency leads to increased membrane fragility and reduced regenerative capacity, contributing to muscle degeneration. The study's methodology could be useful in evaluating the effectiveness of dystrophin gene therapy in mdx mice. The results support the hypothesis that dystrophin's primary role is to reinforce the sarcolemma, protecting it from mechanical stress during muscle contraction. The study also highlights the importance of dystrophin in maintaining muscle integrity and the potential consequences of its deficiency in DMD.