Mouse chimeras and genetic rescue of mosaic muscle.

The nuclear-cytoplasmic relationships existing within mosaic muscle will likely determine whether myoblast transfer can effectively rescue diseased muscle. The mouse chimera preparation is one source of such mosaic muscle in which that in vivo relationship can be investigated in the complete absence of complicating immunological or surgical trauma. For several metabolic enzymes, the mature muscle fiber appears to contain a homogeneous mix of the proteins encoded by multiple myonuclei. This relationship is clearly not representative of all muscle proteins, as several examples of proteins highly localized to "nuclear territories" have now been described. Nonetheless, the intrafiber distribution of certain enzymes, particularly GP1-1, is appropriate for the basis of a genotype marking system applicable to mosaic fibers. In vitro rescue of mdg myotubes is readily achievable by incorporation of few normal myonuclei and possibly by only one. In vivo requirements are apparently far more stringent and an hypothesis in which the mdg gene product, a Ca+(+) channel subunit, is restricted to nuclear territories would be consistent with the disparate results obtained in vitro and in vivo. Finally, chimeras containing mdx/mdx cells may show a partial amelioration of muscle pathology and may provide a means of determining the minimum genetically normal myonuclear compliment required to prevent degeneration of dystrophin-deficient fibers.