Abstract
Cytokines are cell-secreted signaling molecules that modulate various cellular functions, with the best-characterized roles in immune responses. The expression of numerous cytokines in skeletal muscle tissues and muscle cells has been reported, but their function in skeletal myogenesis, the formation of skeletal muscle, has been largely underexplored. To systematically examine the potential roles of cytokines in skeletal myogenesis, we undertook an RNAi screen of 134 mouse cytokine genes for their involvement in the differentiation of C2C12 myoblasts. Our results have uncovered 29 cytokines as strong candidates for novel myogenic regulators, potentially conferring positive and negative regulation at distinct stages of myogenesis. These candidates represent a diverse collection of cytokine families, including interleukins, TNF-related factors, and chemokines. Our findings suggest the fundamental importance of cytokines in the cell-autonomous regulation of myoblast differentiation, and may facilitate future identification of novel therapeutic targets for improving muscle regeneration and growth in health and diseases.
Highlights
During embryonic skeletal myogenesis, cells in somites are guided by various environmental cues to undergo myogenic commitment, and pass along the myogenic pathway by terminal differentiation and fusion to form multinucleated myofibers [1,2]
To search for cytokines potentially involved in myoblast differentiation in a cell-autonomous manner, we carried out an RNAi-based functional screen in mouse C2C12 myoblasts
In determining the coverage of this screen, we did not limit the gene set to those reported to express in skeletal myocytes or muscles. We reasoned that such expression profiling was incomplete at the time of our screen and, in addition, some bona fide myogenic cytokines might be expressed at ultra-low levels in C2C12 cells but functional in those cells, IL-4 being an example
Summary
Cells in somites are guided by various environmental cues to undergo myogenic commitment, and pass along the myogenic pathway by terminal differentiation and fusion to form multinucleated myofibers [1,2]. Injury or other remodeling cues induce satellite cell activation and proliferation, followed by differentiation to form new myofibers or repair existing ones [3]. Skeletal myogenesis in vivo can be largely recapitulated by differentiation of cultured myoblasts, which follows a series of ordered steps including cell cycle withdrawal, myogenic protein expression, cell elongation, migration, and fusion to form myotubes [4]. Cytokines are broadly defined as cell-secreted signaling proteins that modulate cellular functions. The prototypic immunoregulatory cytokine interleukin-4 (IL-4) has been found to be expressed in skeletal myocytes and play a key role in myoblast recruitment and latestage fusion to allow growth of myotubes/myofibers [13]
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