Homer represents a new and diversified family of proteins and comprises several isoforms, Homer 1, 2, and 3; some of these isoforms have been reported to be present in striated muscles. In this paper, the presence of Homer isoforms, referable to 1a, 1b/c/d, 2b and 3, was thoroughly investigated in rat skeletal muscles under resting conditions. Transition in Homer isoforms compositon was studied under experimental conditions of short-term and long-term adaptation, e.g., fatigue and regeneration, respectively. We show that: 1) Homer 1a was constitutively expressed and was transiently up-regulated during regeneration. In C₂C₁₂ cell cultures, Homer 1a was also up-regulated during formation of myotubes. No change of Homer 1a was observed in fatigue; 2) Homer 1b/c/d and Homer 2b were positively and linearly related to muscle mass change during regeneration; 3) Homer 3 was not detectable under resting conditions but was transiently expressed during regeneration although with a temporal pattern distinct from that of Homer 1a. Thus, a switch in Homer isoforms is associated to muscle differentiation and regeneration. Homers may play a role not only in signal transduction of skeletal muscle, in particular regulation of Ca²⁺ release from sarcoplasmic reticulum (Ward CW, Feng W, Tu J, Pessah IN, Worley PF and Schneider MF. Homer protein increases activation of Ca²⁺ sparks in permeabilized skeletal muscle. J Biol Chem 279: 5781-5787, 2004), but also in adaptation.