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Adult skeletal muscle has a remarkable regenerative capacity because of a myogenic progenitor cell population. Using a gene disruption strategy, we determined that Foxk1 regulates myogenic progenitor cell activation and muscle regeneration. In this study, we undertook a yeast two hybrid screen to identify Foxk1 interacting proteins. We identified the LIM‐only protein, Fhl2, as a Foxk1 interacting protein. Using transcriptional assays, we observed that Fhl2, in a dose‐dependent fashion, promotes Foxk1 transcriptional repression of Foxo4 activity. Using histochemical and immunohistochemical assays, we further established that Fhl2 is expressed in the myogenic progenitor cell population. Fhl2 knockdown results in cell cycle arrest, and mice lacking  Fhl2  have perturbed skeletal muscle regeneration. Collectively, these studies define a Fhl2‐Foxk1 cascade that regulates the myogenic progenitor cell activity in adult skeletal muscle and enhances our understanding of muscle regeneration. S TEM  C ELLS  2010;28:462–469

Fhl2 Interacts with Foxk1 and Corepresses Foxo4 Activity in Myogenic Progenitors