You are hereMay 10, 2016 | Muscle Stem Cells
Investigating the Intracellular Regulators of Muscle Stem Cells
Review of “KLF7 regulates satellite cell quiescence in response to extracellular signaling” from Stem Cells by Stuart P. Atkinson
The activation of normally quiescent muscle stem cells, known as satellite cells (SCs), mediates the normal processes of regeneration and repair of adult skeletal muscle. We understand a great deal regarding the extracellular signals which regulate SC quiescence and activation, but less regarding the intracellular mechanisms that respond to these signals.
Recently, a role for Krüppel‐like transcription factors (KLFs) in muscle tissues has become apparent  and this led to the laboratory of Qingwu W. Shen (Northwest A&F University, Yangling, Shaanxi, China) to specifically investigate whether a family member expressed in skeletal muscle (KLF7)  could play a role in regulating SC activity. Their study, published in Stem Cells, now suggests that KLF7 mediates SC quiescence via canonical Notch and TGF‐β signaling and, in doing so, the group provides new insight into the regulation of muscle regeneration .
Initial analysis of KLF7 underscored a key role in SC and muscle cell biology; quiescent mouse SCs and non‐cycling myoblasts expressed high levels of KLF7, which then decreased in activated SCs and proliferating myoblasts. Furthermore, a reduction in KLF7 levels by siRNA mediated an increase in activated proliferating SCs (MyoD+/Pax7+ - See Figure) and promoted myogenic cell cycle progression. Analysis of critical cell cycle modulators determined that KLF7 directly bound to and upregulated p21 expression to mediate cell cycle arrest in SCs and myoblasts and that acetylation of the KLF7 DNA-binding domain modulated promoter binding and transactivation.
But what signaling pathways control KLF7-mediated cell cycle regulation in muscle cells? Further siRNA-mediated downregulation of Tgfbr1 and overexpression of active Notch3 demonstrated that KLF7-dependent TGF‐β signaling blockage and Notch signaling mediated SC quiescence, providing new insight into muscle cell regulatory mechanisms.
Hopefully, these insights into the intracellular mechanisms at play will aid the creation of therapeutic strategies to battle the loss of skeletal muscle function associated with normal aging and myopathy [4-6]. Indeed, the question now stands as to whether dysregulated KLF7 and TGF‐β/Notch signaling can cause premature loss in muscle function and whether we can reverse this using some of the clues uncovered in this study.
- Haldar SM, Ibrahim OA, and Jain MK Kruppel-like Factors (KLFs) in muscle biology. J Mol Cell Cardiol 2007;43:1-10.
- Kawamura Y, Tanaka Y, Kawamori R, et al. Overexpression of Kruppel-like factor 7 regulates adipocytokine gene expressions in human adipocytes and inhibits glucose-induced insulin secretion in pancreatic beta-cell line. Mol Endocrinol 2006;20:844-856.
- Wang X, Shen QW, Wang J, et al. KLF7 Regulates Satellite Cell Quiescence in Response to Extracellular Signaling. Stem Cells 2016;34:1310-1320.
- Jang YC, Sinha M, Cerletti M, et al. Skeletal muscle stem cells: effects of aging and metabolism on muscle regenerative function. Cold Spring Harb Symp Quant Biol 2011;76:101-111.
- Conboy IM, Conboy MJ, Wagers AJ, et al. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 2005;433:760-764.
- Cossu G and Mavilio F Myogenic stem cells for the therapy of primary myopathies: wishful thinking or therapeutic perspective? J Clin Invest 2000;105:1669-1674.