Abstract
Krüppel-like factor 5 (Klf5) is a zinc-finger transcription factor that controls various biological processes, including cell proliferation and differentiation. We show that Klf5 is also an essential mediator of skeletal muscle regeneration and myogenic differentiation. During muscle regeneration after injury (cardiotoxin injection), Klf5 was induced in the nuclei of differentiating myoblasts and newly formed myofibers expressing myogenin in vivo. Satellite cell-specific Klf5 deletion severely impaired muscle regeneration, and myotube formation was suppressed in Klf5-deleted cultured C2C12 myoblasts and satellite cells. Klf5 knockdown suppressed induction of muscle differentiation-related genes, including myogenin. Klf5 ChIP-seq revealed that Klf5 binding overlaps that of MyoD and Mef2, and Klf5 physically associates with both MyoD and Mef2. In addition, MyoD recruitment was greatly reduced in the absence of Klf5. These results indicate that Klf5 is an essential regulator of skeletal muscle differentiation, acting in concert with myogenic transcription factors such as MyoD and Mef2.
Highlights
Skeletal muscle, the dominant organ for locomotion and energy metabolism, has a remarkable capacity for repair and regeneration in response to injury, disease and aging
Scale bar represents 20 mm. (C) Plated satellite cells (SCs) were cultured in growth medium (GM) or differentiating medium (DM; for 2 days or 4 days) after isolation and were co-immunostained for Kruppel-like factor 5 (Klf5) with Pax7 or Myog
Several pieces of evidence gathered in this study clarify the essential role of Klf5 in the control of adult skeletal muscle regeneration
Summary
The dominant organ for locomotion and energy metabolism, has a remarkable capacity for repair and regeneration in response to injury, disease and aging. SC-derived myoblasts undergo differentiation and fusion to form myotubes that replace the damaged myofibers (Comai and Tajbakhsh, 2014), while a subset of activated satellite cells downregulate MyoD, exit the cell cycle to replenish the muscle stem cell pool. A large body of studies have shown that a family of four myogenic regulatory factors (MRFs) regulating early skeletal muscle development regulate the postnatal muscle regeneration program. These MRFs include the myogenic basic-helix-loop-helix type transcription factors MyoD and Myf, which are recruited to skeletal muscle-specific genes regulatory regions, where they determine myogenic fate and initiate the differentiation cascade. Thereafter, MyoD increases the expression of late target genes in cooperation with myogenin and MRF4 through a feed-forward regulatory mechanism
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