In order to determine why the diaphragm is more severely affected by progressive dystrophy than limb muscles in the mdx mouse, we examined how regional variations in diaphragm dystrophy, the measures of disease and repair, proliferation by committed myogenic cells, and the expression of mitogenic basic fibroblast growth factor (bFGF) could contribute to muscle-specific disease phenotypes. There were regional variations in new myotube formation in the diaphragm, with disease more severe in crural than costal leaflets. New repair increased in hyperthyroidism without changes in accumulated repair, probably due to fiber loss. General proliferation was nearly twofold higher in limb than diaphragm mononuclear cells. Since only 2.5-8.4% of committed muscle precursors were proliferating, the higher proliferation by myf5+ myogenic cells in diaphragm did not account for muscle-specific differences. Proliferation by bFGF+ mononuclear cells and an immunogold labeling index for bFGF protein in diaphragm myoblasts were lower in diaphragm than limb muscle. In culture, mixed limb myoblast and fibroblasts contained more S phase cells than diaphragm cells, although myoblasts cycled similarly between muscles. Therefore while muscle architecture and the formation and number of new myotubes certainly affect disease phenotype, the differential outcome of regeneration in mdx diaphragm and limb muscle appears to be contributed by both nonmyogenic and myogenic cells.