Mutations in dystrophin cause Duchenne muscular dystrophy, a severe muscle-wasting disorder. Dystrophin is the scaffold for the dystrophin-glycoprotein complex (DGC), which mechanically links the extracellular matrix to the cytoskeleton in muscle cells. The DGC also binds the enzyme nNOS, which produces the signalling molecule nitric oxide; so, in theory, loss of either the mechanical or the signalling function of the DGC could cause the myofibre degeneration in muscular dystrophy. On p. 1537 Jeffrey Chamberlain and colleagues reveal where the problem lies. They show that expression of a dystrophin isoform that contains the domains necessary for the signalling but not mechanical function of the DGC does not rescue the dystrophic phenotype in a mouse model of muscular dystrophy (mdx mice). Furthermore, they report, the expression of several other truncated dystrophin isoforms that cause mislocalization of nNOS does not correlate with disease severity. The authors therefore conclude that the loss of the mechanical function of the DGC – not signalling – mainly underlies the myofibre death that occurs in dystrophin-deficient muscle.