Abstract
Skeletal myogenesis is orchestrated by distinct regulatory signaling pathways, including PI3K/AKT, that ultimately control muscle gene expression. Recently discovered myogenic micro-RNAs (miRNAs) are deeply implicated in muscle biology. Processing of miRNAs from their primary transcripts is emerging as a major step in the control of miRNA levels and might be well suited to be regulated by extracellular signals. Here we report that the RNA binding protein KSRP is required for the correct processing of primary myogenic miRNAs upon PI3K/AKT activation in myoblasts C2C12 and in the course of injury-induced muscle regeneration, as revealed by Ksrp knock-out mice analysis. PI3K/AKT activation regulates in opposite ways two distinct KSRP functions inhibiting its ability to promote decay of myogenin mRNA and activating its ability to favor maturation of myogenic miRNAs. This dynamic regulatory switch eventually contributes to the activation of the myogenic program.
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Abbreviations
- PI3K:
-
phosphatidylinositol-3-kinase
- miRNAs:
-
microRNAs
- pri-miRNAs:
-
primary miRNA transcripts
- pre-miRNAs:
-
miRNA precursors
- RISC:
-
RNA-induced silencing complex
- 3′UTR:
-
3′ untranslated region
- mRNAs:
-
messenger RNAs
- LY:
-
LY294002
- myr-AKT2:
-
myristoilated constitutively active form of Akt2
- DM:
-
differentiation medium
- GM:
-
growth medium
- myr-AKT2/GM:
-
myr-AKT2 expressing C2C12 cells cultured in GM
- WT:
-
wild-type
- RIP:
-
ribonucleoprotein complexes immunoprecipitation
- DRB:
-
5,6-dichloro-1-β-D-ribofuranosylbenzimidazole, 5,6-dichlorobenzimidazole riboside
References
Yun K, Wold B . Skeletal muscle determination and differentiation: story of a core regulatory network and its context. Curr Opin Cell Biol 1996; 8: 877–889.
Charge SB, Rudnicki MA . Cellular and molecular regulation of muscle regeneration. Physiol Rev 2004; 84: 209–238.
Tedesco FS, Dellavalle A, Diaz-Manera J, Messina G, Cossu G . Repairing skeletal muscle: regenerative potential of skeletal muscle stem cells. J Clin Invest 2010; 120: 11–19.
Tajbakhsh S . Skeletal muscle stem cells in developmental versus regenerative myogenesis. J Intern Med 2009; 266: 372–389.
Guasconi V, Puri PL . Chromatin: the interface between extrinsic cues and the epigenetic regulation of muscle regeneration. Trends Cell Biol 2009; 19: 286–294.
van der Giessen K, Di-Marco S, Clair E, Gallouzi IE . RNAi-mediated HuR depletion leads to the inhibition of muscle cell differentiation. J Biol Chem 2003; 278: 47119–47128.
Figueroa A, Cuadrado A, Fan J, Atasoy U, Muscat GE, Muñoz-Canoves P et al. Role of HuR in skeletal myogenesis through coordinate regulation of muscle differentiation genes. Mol Cell Biol 2003; 23: 4991–5004.
Briata P, Forcales SV, Ponassi M, Corte G, Chen CY, Karin M et al. p38-dependent phosphorylation of the mRNA decay-promoting factor KSRP controls the stability of select myogenic transcripts. Mol Cell 2005; 20: 891–903.
Gherzi R, Trabucchi M, Ponassi M, Gallouzi IE, Rosenfeld MG, Briata P . Akt2-mediated phosphorylation of Pitx2 controls Ccnd1 mRNA decay during muscle cell differentiation. Cell Death Differ 2010; 17: 975–983.
Williams AH, Liu N, van Rooij E, Olson EN . MicroRNA control of muscle development and disease. Curr Opin Cell Biol 2009; 21: 461–469.
Güller I, Russell AP . MicroRNAs in skeletal muscle: their role and regulation in development, disease and function. J Physiol 2010; 588: 4075–4087.
Chen JF, Mandel EM, Thomson JM, Wu Q, Callis TE, Hammond SM et al. The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nat Genet 2006; 38: 228–233.
Kim HK, Lee YS, Sivaprasad U, Malhotra A, Dutta A . Muscle-specific microRNA miR-206 promotes muscle differentiation. J Cell Biol 2006; 174: 677–687.
Rao PK, Kumar RM, Farkhondeh M, Baskerville S, Lodish HF . Myogenic factors that regulate expression of muscle-specific microRNAs. Proc Natl Acad Sci USA 2006; 103: 8721–8726.
Taulli R, Bersani F, Foglizzo V, Linari A, Vigna E, Ladanyi M et al. The muscle-specific microRNA miR-206 blocks human rhabdomyosarcoma growth in xenotransplanted mice by promoting myogenic differentiation. J Clin Invest 2009; 119: 2366–2378.
Elia L, Contu R, Quintavalle M, Varrone F, Chimenti C, Russo MA et al. Reciprocal regulation of microRNA-1 and insulin-like growth factor-1 signal transduction cascade in cardiac and skeletal muscle in physiological and pathological conditions. Circulation 2009; 120: 2377–2385.
Cacchiarelli D, Martone J, Girardi E, Cesana M, Incitti T, Morlando M et al. MicroRNAs involved in molecular circuitries relevant for the Duchenne muscular dystrophy pathogenesis are controlled by the dystrophin/nNOS pathway. Cell Metab 2010; 12: 341–351.
Krol J, Loedige I, Filipowicz W . The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet 2010; 11: 597–610.
Fabian MR, Sonenberg N, Filipowicz W . Regulation of mRNA translation and stability by microRNAs. Annu Rev Biochem 2010; 79: 351–379.
Newman MA, Hammond SM . Emerging paradigms of regulated microRNA processing. Genes Dev 2010; 24: 1086–1092.
Thomson JM, Newman M, Parker JS, Morin-Kensicki EM, Wright T, Hammond SM . Extensive post-transcriptional regulation of microRNAs and its implications for cancer. Genes Dev 2006; 20: 2202–2207.
Kumar MS, Lu J, Mercer KL, Golub TR, Jacks T . Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nat Genet 2007; 39: 673–677.
O’Rourke JR, Georges SA, Seay HR, Tapscott SJ, McManus MT, Goldhamer DJ et al. Essential role for Dicer during skeletal muscle development. Dev Biol 2007; 311: 359–368.
Paroo Z, Ye X, Chen S, Liu Q . Phosphorylation of the human microRNA-generating complex mediates MAPK/Erk signaling. Cell 2009; 139: 112–122.
Trabucchi M, Briata P, Filipowicz W, Rosenfeld MG, Ramos A, Gherzi R . How to control miRNA maturation? RNA Biol 2009; 6: 536–540.
Briata P, Chen CY, Giovarelli M, Pasero M, Trabucchi M, Ramos A et al. KSRP, many functions for a single protein. Front Biosci 2011; 16: 1787–1796.
Trabucchi M, Briata P, Garcia-Mayoral M, Haase AD, Filipowicz W, Ramos A et al. The RNA-binding protein KSRP promotes the biogenesis of a subset of microRNAs. Nature 2009; 459: 1010–1014.
Ruggiero T, Trabucchi M, De Santa F, Zupo S, Harfe BD, McManus MT et al. LPS induces KH-type splicing regulatory protein-dependent processing of microRNA-155 precursors in macrophages. FASEB J 2009; 23: 2898–2908.
Zhang X, Wan G, Berger FG, He X, Lu X . The ATM kinase induces microRNA biogenesis in the DNA damage response. Mol Cell 2011; 41: 371–383.
Gherzi R, Trabucchi M, Ponassi M, Ruggiero T, Corte G, Moroni C et al. The RNA-binding protein KSRP promotes decay of beta-catenin mRNA and is inactivated by PI3K-AKT signaling. PLoS Biol 2006; 5: e5.
Serra C, Palacios D, Mozzetta C, Forcales SV, Morantte I, Ripani M et al. Functional interdependence at the chromatin level between the MKK6/p38 and IGF1/PI3K/AKT pathways during muscle differentiation. Mol Cell 2007; 28: 200–213.
Brugge J, Hung MC, Mills GB . A new mutational AKTivation in the PI3K pathway. Cancer Cell 2007; 12: 104–107.
Rotwein P, Wilson EM . Distinct actions of Akt1 and Akt2 in skeletal muscle differentiation. J Cell Physiol 2009; 219: 503–511.
Conejo R, Lorenzo M . Insulin signaling leading to proliferation, survival, and membrane ruffling in C2C12 myoblasts. J Cell Physiol 2001; 187: 96–108.
Anderson C, Catoe H, Werner R . MIR-206 regulates connexin43 expression during skeletal muscle development. Nucleic Acids Res 2006; 34: 5863–5871.
Lin WJ, Zheng X, Lin CC, Tsao J, Zhu X, Cody JJ et al. Post-transcriptional control of type I interferon genes by KSRP in the innate immune response against viral infection. Mol Cell Biol 2011; 31: 3196–3207.
Schiaffino S, Mammucari C . Regulation of skeletal muscle growth by the IGF1-Akt/PKB pathway: insights from genetic models. Skeletal Muscle 2011; 1: 4.
Yuasa K, Hagiwara Y, Ando M, Nakamura A, Takeda S, Hijikata T . MicroRNA-206 is highly expressed in newly formed muscle fibers: implications regarding potential for muscle regeneration and maturation in muscular dystrophy. Cell Struct Funct 2008; 33: 163–169.
Iliopoulos D, Polytarchou C, Hatziapostolou M, Kottakis F, Maroulakou IG, Struhl K et al. MicroRNAs differentially regulated by Akt isoforms control EMT and stem cell renewal in cancer cells. Sci Signal 2009; 2: ra62.
Sayed D, Abdellatif M . AKT-ing via microRNA. Cell Cycle 2010; 9: 3213–3217.
Michlewski G, Cáceres JF . Antagonistic role of hnRNP A1 and KSRP in the regulation of let-7a biogenesis. Nat Struct Mol Biol 2010; 17: 1011–1018.
Acknowledgements
Part of the studies has been conducted in the laboratories and facilities of the Centro Biotecnologie Avanzate (CBA, Genova, Italy). This work has been partly supported by Associazione Italiana per la Ricerca sul Cancro (AIRC), Association for International Cancer research (AICR grant no. 10-0527) and Limonte 2 (Regione Liguria, RNA Technology) to RG; the work of MP is supported by AICR grant no. 10-0527. We are indebted with Drs. Imed E Gallouzi (McGill University) for providing us the cardiotoxin protocol and Zhenguo Wu (Hong Kong University of Science & Technology) for useful discussions.
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Briata, P., Lin, WJ., Giovarelli, M. et al. PI3K/AKT signaling determines a dynamic switch between distinct KSRP functions favoring skeletal myogenesis. Cell Death Differ 19, 478–487 (2012). https://doi.org/10.1038/cdd.2011.117
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DOI: https://doi.org/10.1038/cdd.2011.117
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