MYOGENESIS IL-4: A Fusion Signal

One function of the cytokine interleukin 4 (IL-4) when released by T cells is to stimulate macrophage fusion. Horsley et al. show that IL-4 is also a fusion-stimulating signal for nascent myotubes and promotes myotube growth by enhancing fusion of myoblasts to existing myotubes. Calcium signaling is essential for muscle differentiation and one family of transcription factors activated by calcium is the nuclear factor of activated T cells (NFAT). Several NFAT isoforms are temporally activated during myogenesis, but NFAT2c is the isoform specifically activated in nascent myotubes just after fusion. Using NFAT2c^-/- myoblasts, the authors showed that myotube size and nuclei number could be restored to wild-type amounts by application of IL-4. Furthermore, IL-4 expression and secretion was increased during the period following initial myotube formation and was absent in the NFAT2c^-/- myotube cultures resulting in smaller (narrower) myotubes with fewer nuclei. The importance of IL-4 and the IL-4 receptor (IL-4R) was confirmed in that IL-4^-/- or IL-4R^-/- mouse muscles showed decreased myofiber size and myotube nuclei number compared with wild-type muscle. Using a coculture fusion assay, the authors showed that the myotube-released IL-4 stimulated the IL-4R-expressing myoblasts to fuse with existing myotubes. Thus, these experiments not only address fundamental questions in muscle development and recovery from injury, but also provide a role for IL-4 outside of the immune system.

V. Horsley, K. M. Jansen, S. T. Mills, G. K. Pavlath, IL-4 acts as a myoblast recruitment factor during mammalian muscle growth. Cell 113, 483-494 (2003). [Online Journal]