Identification of a role for Janus kinase2 (JAK2) in skeletal muscle mitogenesis, myogenesis, and hypertrophy

Abstract

<p>Skeletal muscle is a dynamic tissue with tight developmental control and the ability to significantly remodel in the postnatal animal. Understanding the molecular mechanisms underlying skeletal muscle development and postnatal growth is critical to potential therapeutic manipulation. Janus kinase2 (JAK2) is a tyrosine kinase critical for growth of numerous cell types and is causative in many cancers, including leukemia. In this study we sought to understand the role of the JAK/STAT signaling cascade in skeletal muscle. In particular, this research focused on the role of JAK2 in skeletal muscle mitogenesis, myogenesis, and hypertrophy. Little work has been done regarding the role of JAK2 in skeletal muscle and, to date, no studies have analyzed a possible function for JAK2 in skeletal muscle myogenesis or hypertrophy. With this work we demonstrate that JAK2 is involved in the regulation of normal proliferation of C2C12 myoblasts. Our work also suggests a unique role for JAK2 in myogenesis. Strikingly, experiments demonstrated that, in C2C12 myoblasts, JAK2 was located in the nucleus. This in contrast to the current paradigm of JAK2 signaling at the plasma membrane bound to receptors lacking intrinsic kinase abilities. However, in terminally differentiated myotubes, JAK2 is located throughout the cell. These results represent the first characterization of a necessary and sufficient requirement for JAK2 in myoblast proliferation and suggest a novel role for JAK2 protein in skeletal muscle myogenesis. In addition, JAK2 was identified to have a potential role in skeletal muscle hypertrophy. Previous work demonstrated that JAK2 expression increased following three days of work overload in skeletal muscle. To investigate this role, activation of the JAK/STAT pathway was studied in vitro using a cyclic stretch model. This study identified the JAK2/STAT signaling cascade as activated by mechanical stretch of C2C12 myoblasts. Cyclic stretch results in the activation of JAK2, STAT1, and STAT5. In addition, active JAK2 is required for stretch-induced proliferation of C2C12 myoblasts. The results of this study establish that JAK2 is a critical signaling protein in the control of skeletal muscle cells. In addition, it identifies that JAK/STAT pathway as a potential therapeutic target for skeletal muscle manipulation.</p>