Srf-Dependent Paracrine Signals Produced by Myofibers Control Satellite Cell-Mediated Skeletal Muscle Hypertrophy

Aline Guerci, Charlotte Lahoute, Sophie Hébrard, Laura Collard, Dany Graindorge, Maryline Favier, Nicolas Cagnard, Sabrina Batonnet-Pichon, Guillaume Précigout, Luis Garcia, David Tuil, Dominique Daegelen, Athanassia Sotiropoulos

Adult skeletal muscles adapt their fiber size to workload. We show that serum response factor (Srf) is required for satellite cell-mediated hypertrophic muscle growth. Deletion of Srf from myofibers and not satellite cells blunts overload-induced hypertrophy, and impairs satellite cell proliferation and recruitment to pre-existing fibers. We reveal a gene network in which Srf within myofibers modulates interleukin-6 and cyclooxygenase-2/interleukin-4 expressions and therefore exerts a paracrine control of satellite cell functions. In Srf-deleted muscles, in vivo overexpression of interleukin-6 is sufficient to restore satellite cell proliferation but not satellite cell fusion and overall growth. In contrast cyclooxygenase-2/interleukin-4 overexpression rescue satellite cell recruitment and muscle growth without affecting satellite cell proliferation, identifying altered fusion as the limiting cellular event. These findings unravel a role for Srf in the translation of mechanical cues applied to myofibers into paracrine signals, which in turn will modulate satellite cell functions and support muscle growth.

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