Myogenesis involves a conserved program of muscle gene isoform switching requiring the synchronized induction and repression of numerous muscle-specific gene family members. Central to understanding the regulation of this process are questions related to the origin and transmission of regulatory signals to the myofiber. We show here that troponin T gene switching can be precociously initiated by extrinsic blood-borne components but also requires other mechanisms that are regulated locally, intrinsically, or posttranscriptionally. We established a chimeric blood circulation by parabiosis between fetal chicks and quails to determine whether signals inducing earlier troponin T mRNA isoform switching in quails could be transduced to chick partners through the serum. While quail fetuses were unaffected by parabiosis, quail serum caused premature troponin T iso-mRNA switching in chick muscle, although initiation remained later than in quails. The onset of repression of a known innervation-dependent acetylcholine receptor mRNA did not coincide with the initiation of troponin T iso-mRNA switching and was not affected by parabiosis. These results support serum-borne factor regulation of isoform switching as an important and distinct mechanism relevant to understanding how extrinsic and intrinsic cues are integrated during muscle differentiation and development.