Prox1 transcription factor regulates satellite cell and skeletal muscle fiber phenotype and function

Abstract

Prospero related homeobox 1 (Prox1) transcription factor is important for the development of several organs, including the heart, liver and lymphatic vessels. Prox1 gene polymorphisms have recently been related to insulin resistance. We show here that Prox1 is expressed in adult slow skeletal muscle fibers and satellite cells, both in rodents and in humans. Prox1 expression is increased during mouse C2C12 cell differentiation and in primary human myoblast differentiation into myotubes, and its silencing leads to failure in differentiation. Mechanistically, Prox1 activates calcineurin signaling both in vivo in skeletal muscles and in C2C12 cells. Overexpression of Prox1 in fast skeletal muscle induced the expression of slow muscle fiber-related myofibrillar and calcium-signaling genes, while deletion of Prox1 lead to the upregulation of the fast myosin heavy chain isoforms in slow soleus muscle. With lineage tracing, we showed that Prox1 expressing satellite cells proliferate and contribute to muscle regeneration after cardiotoxin-induced muscle injury. After acute running exercise, the expression of Prox1 was downregulated in mouse gastrocnemius muscle. We have identified Prox1 as an important transcription factor regulating mammalian skeletal muscle fiber type and satellite cell differentiation and phenotype. This provides novel information how skeletal muscle function is regulated, and is important in terms of understanding normal skeletal muscle physiology and muscle diseases.