Fibro-adipogenic Progenitors of Dystrophic Mice Are Insensitive to NOTCH Regulation of Adipogenesis

Overview

Journal Life Sci Alliance

Specialties Biochemistry
Biology
Cell Biology
Molecular Biology

Date 2019 Jun 27

PMID 31239312

Citations 37

Authors

Milica Marinkovic

Claudia Fuoco

Francesca Sacco

Andrea Cerquone Perpetuini

Giulio Giuliani

Elisa Micarelli

Theodora Pavlidou

Lucia Lisa Petrilli

Alessio Reggio

Federica Riccio

Filomena Spada

Simone Vumbaca

Alessandro Zuccotti

Luisa Castagnoli

Matthias Mann

Cesare Gargioli

Gianni Cesareni

Affiliations

Soon will be listed here.

Abstract

Fibro-adipogenic progenitors (FAPs) promote satellite cell differentiation in adult skeletal muscle regeneration. However, in pathological conditions, FAPs are responsible for fibrosis and fatty infiltrations. Here we show that the NOTCH pathway negatively modulates FAP differentiation both in vitro and in vivo. However, FAPs isolated from young dystrophin-deficient mice are insensitive to this control mechanism. An unbiased mass spectrometry-based proteomic analysis of FAPs from muscles of wild-type and mice suggested that the synergistic cooperation between NOTCH and inflammatory signals controls FAP differentiation. Remarkably, we demonstrated that factors released by hematopoietic cells restore the sensitivity to NOTCH adipogenic inhibition in FAPs. These results offer a basis for rationalizing pathological ectopic fat infiltrations in skeletal muscle and may suggest new therapeutic strategies to mitigate the detrimental effects of fat depositions in muscles of dystrophic patients.

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References

DiMario J, Uzman A, Strohman R . Fiber regeneration is not persistent in dystrophic (MDX) mouse skeletal muscle. Dev Biol. 1991; 148(1):314-21. DOI: 10.1016/0012-1606(91)90340-9. View

Jiao Z, Wang W, Ma J, Wang S, Su Z, Xu H . Notch signaling mediates TNF-α-induced IL-6 production in cultured fibroblast-like synoviocytes from rheumatoid arthritis. Clin Dev Immunol. 2011; 2012:350209. PMC: 3235448. DOI: 10.1155/2012/350209. View

Lemos D, Babaeijandaghi F, Low M, Chang C, Lee S, Fiore D . Nilotinib reduces muscle fibrosis in chronic muscle injury by promoting TNF-mediated apoptosis of fibro/adipogenic progenitors. Nat Med. 2015; 21(7):786-94. DOI: 10.1038/nm.3869. View

van Rooijen N, Sanders A . Liposome mediated depletion of macrophages: mechanism of action, preparation of liposomes and applications. J Immunol Methods. 1994; 174(1-2):83-93. DOI: 10.1016/0022-1759(94)90012-4. View

Gaeta M, Messina S, Mileto A, Vita G, Ascenti G, Vinci S . Muscle fat-fraction and mapping in Duchenne muscular dystrophy: evaluation of disease distribution and correlation with clinical assessments. Preliminary experience. Skeletal Radiol. 2011; 41(8):955-61. DOI: 10.1007/s00256-011-1301-5. View

Pretheeban T, Lemos D, Paylor B, Zhang R, Rossi F . Role of stem/progenitor cells in reparative disorders. Fibrogenesis Tissue Repair. 2012; 5(1):20. PMC: 3541267. DOI: 10.1186/1755-1536-5-20. View

Joe A, Yi L, Natarajan A, Le Grand F, So L, Wang J . Muscle injury activates resident fibro/adipogenic progenitors that facilitate myogenesis. Nat Cell Biol. 2010; 12(2):153-63. PMC: 4580288. DOI: 10.1038/ncb2015. View

Radley H, Davies M, Grounds M . Reduced muscle necrosis and long-term benefits in dystrophic mdx mice after cV1q (blockade of TNF) treatment. Neuromuscul Disord. 2008; 18(3):227-38. DOI: 10.1016/j.nmd.2007.11.002. View

Yin H, Price F, Rudnicki M . Satellite cells and the muscle stem cell niche. Physiol Rev. 2013; 93(1):23-67. PMC: 4073943. DOI: 10.1152/physrev.00043.2011. View

10.

Mourikis P, Sambasivan R, Castel D, Rocheteau P, Bizzarro V, Tajbakhsh S . A critical requirement for notch signaling in maintenance of the quiescent skeletal muscle stem cell state. Stem Cells. 2011; 30(2):243-52. DOI: 10.1002/stem.775. View

11.

Parmentier-Decrucq E, Duhamel A, Ernst O, Fermont C, Louvet A, Vernier-Massouille G . Effects of infliximab therapy on abdominal fat and metabolic profile in patients with Crohn's disease. Inflamm Bowel Dis. 2009; 15(10):1476-84. DOI: 10.1002/ibd.20931. View

12.

Bjornson C, Cheung T, Liu L, Tripathi P, Steeper K, Rando T . Notch signaling is necessary to maintain quiescence in adult muscle stem cells. Stem Cells. 2011; 30(2):232-42. PMC: 3384696. DOI: 10.1002/stem.773. View

13.

Kawanishi N, Mizokami T, Niihara H, Yada K, Suzuki K . Macrophage depletion by clodronate liposome attenuates muscle injury and inflammation following exhaustive exercise. Biochem Biophys Rep. 2017; 5:146-151. PMC: 5600362. DOI: 10.1016/j.bbrep.2015.11.022. View

14.

Mozzetta C, Consalvi S, Saccone V, Tierney M, Diamantini A, Mitchell K . Fibroadipogenic progenitors mediate the ability of HDAC inhibitors to promote regeneration in dystrophic muscles of young, but not old Mdx mice. EMBO Mol Med. 2013; 5(4):626-39. PMC: 3628105. DOI: 10.1002/emmm.201202096. View

15.

de Vera I, Zheng J, Novick S, Shang J, Hughes T, Brust R . Synergistic Regulation of Coregulator/Nuclear Receptor Interaction by Ligand and DNA. Structure. 2017; 25(10):1506-1518.e4. PMC: 5653230. DOI: 10.1016/j.str.2017.07.019. View

16.

Bodenmiller B, Zunder E, Finck R, Chen T, Savig E, Bruggner R . Multiplexed mass cytometry profiling of cellular states perturbed by small-molecule regulators. Nat Biotechnol. 2012; 30(9):858-67. PMC: 3627543. DOI: 10.1038/nbt.2317. View

17.

Chakkalakal J, Jones K, Basson M, Brack A . The aged niche disrupts muscle stem cell quiescence. Nature. 2012; 490(7420):355-60. PMC: 3605795. DOI: 10.1038/nature11438. View

18.

Perfetto L, Briganti L, Calderone A, Cerquone Perpetuini A, Iannuccelli M, Langone F . SIGNOR: a database of causal relationships between biological entities. Nucleic Acids Res. 2015; 44(D1):D548-54. PMC: 4702784. DOI: 10.1093/nar/gkv1048. View

19.

Amir E, Davis K, Tadmor M, Simonds E, Levine J, Bendall S . viSNE enables visualization of high dimensional single-cell data and reveals phenotypic heterogeneity of leukemia. Nat Biotechnol. 2013; 31(6):545-52. PMC: 4076922. DOI: 10.1038/nbt.2594. View

20.

Fazio C, Ricciardiello L . Inflammation and Notch signaling: a crosstalk with opposite effects on tumorigenesis. Cell Death Dis. 2016; 7(12):e2515. PMC: 5260996. DOI: 10.1038/cddis.2016.408. View