Ciliary Hedgehog Signaling Restricts Injury-Induced Adipogenesis
Open accessAbstract
Injured skeletal muscle regenerates, but with age or in muscular dystrophies, muscle is replaced by fat. Upon injury, muscle-resident fibro/adipogenic progenitors (FAPs) proliferated and gave rise to adipocytes. These FAPs dynamically produced primary cilia, structures that transduce intercellular cues such as Hedgehog (Hh) signals. Genetically removing cilia from FAPs inhibited intramuscular adipogenesis, both after injury and in a mouse model of Duchenne muscular dystrophy. Blocking FAP ciliation also enhanced myofiber regeneration after injury and reduced myofiber size decline in the muscular dystrophy model. Hh signaling through FAP cilia regulated the expression of TIMP3, a secreted metalloproteinase inhibitor, that inhibited MMP14 to block adipogenesis. A pharmacological mimetic of TIMP3 blocked the conversion of FAPs into adipocytes, pointing to a strategy to combat fatty degeneration of skeletal muscle. We conclude that ciliary Hh signaling by FAPs orchestrates the regenerative response to skeletal muscle injury.
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PDGFRα is principally localized to primary cilia, although non-ciliary localizations have been reported for specific cell types.
“PDGFRα is principally localized to primary cilia 225, 240–243, although non-ciliary localizations for this isoform have been reported for specific cell types 243–245.”
From Cellular signalling by primary cilia in development, organ function and disease (2019) · cites this paper as [245]
The Results section, “FAPs are dynamically ciliated during muscle regeneration” (page unavailable), says that PDGFRα-expressing FAPs are frequently ciliated. That describes the cells, not where PDGFRα itself is located. Searches for ciliary and non-ciliary PDGFRα localization found no passage addressing either part of the claim. (LLM, conf=0.75)
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Cites
Analyzing real-time PCR data by the comparative CT method
Schmittgen, T. D., & Livak, K. J. (2008) · Nature Protocols · doi:10.1038/nprot.2008.73 · Cited by 26,190 · see citing works
Dystrophin: the protein product of the Duchenne muscular dystrophy locus
Hoffman, E. P., Brown, R. H., & Kunkel, L. M. (1987) · Cell · doi:10.1016/0092-8674(87)90579-4 · Cited by 4,693 · see citing works
Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus
Srinivas, S., Watanabe, T., Lin, C.-S., William, C. M., Tanabe, Y., Jessell, T. M., & Costantini, F. (2001) · BMC Developmental Biology · doi:10.1186/1471-213x-1-4 · Cited by 3,121 · see citing works
The primary cilium: a signalling centre during vertebrate development
Goetz, S. C., & Anderson, K. V. (2010) · Nature Reviews Genetics · doi:10.1038/nrg2774 · Cited by 1,824 · see citing works
X chromosome-linked muscular dystrophy (mdx) in the mouse
Bulfield, G., Siller, W. G., Wight, P. A., & Moore, K. J. (1984) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.81.4.1189 · Cited by 1,765 · see citing works
Altered Neural Cell Fates and Medulloblastoma in Mouse <i>patched</i> Mutants
Goodrich, L. V., Milenković, L., Higgins, K. M., & Scott, M. P. (1997) · Science · doi:10.1126/science.277.5329.1109 · Cited by 1,696 · see citing works
Muscle injury activates resident fibro/adipogenic progenitors that facilitate myogenesis
Joe, A. W. B., Yi, L., Natarajan, A., Le Grand, F., So, L., Wang, J., Rudnicki, M. A., & Rossi, F. M. V. (2010) · Nature Cell Biology · doi:10.1038/ncb2015 · Cited by 1,690 · see citing works
Mitchell, W. K., Williams, J., Atherton, P., Larvin, M., Lund, J., & Narici, M. (2012) · Frontiers in Physiology · doi:10.3389/fphys.2012.00260 · Cited by 1,377 · see citing works
Uezumi, A., Fukada, S., Yamamoto, N., Takeda, S., & Tsuchida, K. (2010) · Nature Cell Biology · doi:10.1038/ncb2014 · Cited by 1,315 · see citing works
Small molecule modulation of Smoothened activity
Chen, J., Taipale, J., Young, K. E., Maiti, T., & Beachy, P. A. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.182542899 · Cited by 991 · see citing works
Perivascular Gli1+ Progenitors Are Key Contributors to Injury-Induced Organ Fibrosis
Kramann, R., Schneider, R. K., DiRocco, D. P., Machado, F., Fleig, S., Bondzie, P. A., Henderson, J. M., Ebert, B. L., & Humphreys, B. D. (2015) · Cell Stem Cell · doi:10.1016/j.stem.2014.11.004 · Cited by 922 · see citing works
Type 2 Innate Signals Stimulate Fibro/Adipogenic Progenitors to Facilitate Muscle Regeneration
Heredia, J. E., Mukundan, L., Chen, F. M., Mueller, A. A., Deo, R. C., Locksley, R. M., Rando, T. A., & Chawla, A. (2013) · Cell · doi:10.1016/j.cell.2013.02.053 · Cited by 818 · see citing works
Kang, S., Fukaya, M., Yang, J. K., Rothstein, J., & Bergles, D. (2010) · Neuron · doi:10.1016/j.neuron.2010.09.009 · Cited by 778 · see citing works
Lemos, D. R., Babaeijandaghi, F., Low, M., Chang, C.-K., Lee, S. T., Fiore, D., Zhang, R.-H., Natarajan, A., Nedospasov, S. A., & Rossi, F. M. V. (2015) · Nature Medicine · doi:10.1038/nm.3869 · Cited by 740 · see citing works
Gli Proteins in Development and Disease
Hui, C., & Angers, S. (2011) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-092910-154048 · Cited by 693 · see citing works
Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletal muscle
Uezumi, A., Ito, T., Morikawa, D., Shimizu, N., Yoneda, T., Segawa, M., Yamaguchi, M., Ogawa, R., Matev, M. M., Miyagoe-Suzuki, Y., et al. (2011) · Journal of Cell Science · doi:10.1242/jcs.086629 · Cited by 680 · see citing works
Qi, J. H., Ebrahem, Q., Moore, N., Murphy, G., Claesson-Welsh, L., Bond, M., Baker, A., & Anand-Apte, B. (2003) · Nature Medicine · doi:10.1038/nm846 · Cited by 658 · see citing works
Adipocyte extracellular matrix composition, dynamics and role in obesity
Mariman, E. C. M., & Wang, P. (2010) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-010-0263-4 · Cited by 561 · see citing works
Metalloproteinases and their natural inhibitors in inflammation and immunity
Khokha, R., Murthy, A., & Weiss, A. (2013) · Nature reviews. Immunology · doi:10.1038/nri3499 · Cited by 552 · see citing works
Liu, A., Wang, B., & Niswander, L. A. (2005) · Development · doi:10.1242/dev.01894 · Cited by 536 · see citing works
Brownell, I., Guevara, E., Bai, C. B., Loomis, C. A., & Joyner, A. L. (2011) · Cell stem cell · doi:10.1016/j.stem.2011.02.021 · Cited by 453 · see citing works
Carine Chavey, A., Mari, B. P., Monthouel, M.-N., Bonnafous, S., Anglard, P., OBBERGHEN, E. V., & Tartare‐Deckert, S. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m209196200 · Cited by 447 · see citing works
May, S., Ashique, A. M., Karlén, M., Wang, B., Shen, Y., Zarbalis, K., Reiter, J. F., Ericson, J., & Peterson, A. S. (2005) · Developmental Biology · doi:10.1016/j.ydbio.2005.08.050 · Cited by 428 · see citing works
Self-citationIntraflagellar transport is essential for endochondral bone formation
Haycraft, C. J., Zhang, Q., Song, B., Jackson, W. S., Detloff, P. J., Serra, R. A., & Yoder, B. K. (2006) · Development · doi:10.1242/dev.02732 · Cited by 395 · see citing works
Transit-Amplifying Cells Orchestrate Stem Cell Activity and Tissue Regeneration
Hsu, Y., Li, L., & Fuchs, E. V. (2014) · Cell · doi:10.1016/j.cell.2014.02.057 · Cited by 379 · see citing works
A Pericellular Collagenase Directs the 3-Dimensional Development of White Adipose Tissue
Chun, T.-H., Hotary, K. B., Sabeh, F., Saltiel, A. R., Allen, E. D., & Weiss, S. J. (2006) · Cell · doi:10.1016/j.cell.2006.02.050 · Cited by 378 · see citing works
Pospisilik, J. A., Schramek, D., Schnidar, H., Cronin, S. J. F., Nehme, N. T., Zhang, X., Knauf, C., Cani, P. D., Aumayr, K., Todoric, J., et al. (2010) · Cell · doi:10.1016/j.cell.2009.12.027 · Cited by 368 · see citing works
Selective Inhibition of Matrix Metalloproteinase-14 Blocks Tumor Growth, Invasion, and Angiogenesis
Devy, L., Huang, L., Naa, L., Yanamandra, N., Pieters, H., Frans, N., Chang, E. Q., Tao, Q., Vanhove, M., Lejeune, A., et al. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-3255 · Cited by 356 · see citing works
Montani, J.-P., Carroll, J. F., Dwyer, T. M., Antic, V., Yang, Z., & Dulloo, A. G. (2004) · International Journal of Obesity · doi:10.1038/sj.ijo.0802858 · Cited by 294 · see citing works
Hedgehog signaling plays a conserved role in inhibiting fat formation
Suh, J. M., Gao, X., McKay, J., McKay, R. M., Salo, Z., & Graff, J. M. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2005.11.012 · Cited by 271 · see citing works
Pancreatic Ectopic Fat Is Characterized by Adipocyte Infiltration and Altered Lipid Composition
Pinnick, K. E., Collins, S., Londos, C., Gauguier, D., Clark, A., & Fielding, B. A. (2008) · Obesity · doi:10.1038/oby.2007.110 · Cited by 220 · see citing works
Hotary, K. B., Yana, I., Sabeh, F., Li, X.-Y., Holmbeck, K., Birkedal‐Hansen, H., Allen, E. D., Hiraoka, N., & Weiss, S. J. (2002) · The Journal of Experimental Medicine · doi:10.1084/jem.20010815 · Cited by 217 · see citing works
Cellular and Molecular Mechanisms Regulating Fibrosis in Skeletal Muscle Repair and Disease
Serrano, A. L., Mann, C. J., Vidal, B., Ardite, E., Perdiguero, E., & Muñoz-Cánoves, P. (2011) · Current Topics in Developmental Biology · doi:10.1016/b978-0-12-385940-2.00007-3 · Cited by 200 · see citing works
Kopinke, D., Brailsford, M., Shea, J., Leavitt, R., Scaife, C. L., & Murtaugh, L. C. (2011) · Development · doi:10.1242/dev.053843 · Cited by 192 · see citing works
Self-citationMarion, V., Stoetzel, C., Schlicht, D., Messaddeq, N., Koch, M., Flori, E., Danse, J. M., Mandel, J.-L., & Dollfus, H. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0812518106 · Cited by 178 · see citing works
Regeneration after cardiotoxin injury of innervated and denervated slow and fast muscles of mammals
d’Albis, A., Couteaux, R., Janmot, C., Roulet, A., & Mira, J. (1988) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1988.tb14068.x · Cited by 175 · see citing works
Macaulay, V. M., O'Byrne, K. J., Saunders, M. P., et al. (1999) · PubMed · Cited by 161 · see citing works
Zhu, D., Shi, S., Wang, H., & Liao, K. (2009) · Journal of Cell Science · doi:10.1242/jcs.046276 · Cited by 156 · see citing works
Sonic hedgehog regulates angiogenesis and myogenesis during post‐natal skeletal muscle regeneration
Straface, G., Aprahamian, T. R., Flex, A., Gaetani, E., Biscetti, F., Smith, R. C., Pecorini, G., Pola, E., Angelini, F., Stigliano, E., et al. (2008) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2008.00440.x · Cited by 134 · see citing works
Novel genes regulated by Sonic Hedgehog in pluripotent mesenchymal cells
Ingram, W. J., Wicking, C., Grimmond, S. M., Forrest, A. R. R., & Wainwright, B. J. (2002) · Oncogene · doi:10.1038/sj.onc.1205975 · Cited by 122 · see citing works
Patched 1 conditional null allele in mice
Ellis, T., Smyth, I., Riley, E., Graham, S., Elliot, K., Narang, M. A., Kay, G. F., Wicking, C., & Wainwright, B. J. (2003) · genesis · doi:10.1002/gene.10208 · Cited by 105 · see citing works
Dulor, J. P., Cambon, B., Vigneron, P., et al. (1998) · FEBS Letters · doi:10.1016/s0014-5793(98)01216-2 · Cited by 98 · see citing works
Mouse model of skeletal muscle adiposity: A glycerol treatment approach
Pisani, D. F., Bottema, C. D. K., Butori, C., Dani, C., & Dechesne, C. A. (2010) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2010.05.021 · Cited by 83 · see citing works
A Small-Molecule Smoothened Agonist Prevents Glucocorticoid-Induced Neonatal Cerebellar Injury
Heine, V. M., Griveau, A., Chapin, C. J., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002731 · Cited by 83 · see citing works
Ongoing Notch signaling maintains phenotypic fidelity in the adult exocrine pancreas
Kopinke, D., Brailsford, M., Pan, F. C., Magnuson, M. A., Wright, C. V. E., & Murtaugh, L. C. (2011) · Developmental Biology · doi:10.1016/j.ydbio.2011.11.010 · Cited by 82 · see citing works
Self-citationAutonomous and nonautonomous roles of Hedgehog signaling in regulating limb muscle formationPreprint
Hu, J. K., McGlinn, E., Harfe, B. D., et al. (2012) · Genes & Development · doi:10.1101/gad.187385.112 · Cited by 63 · see citing works
Wei, S., Kashiwagi, M., Kota, S., Xie, Z., Nagase, H., & Brew, K. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.c500220200 · Cited by 59 · see citing works
Transcriptional regulation of graded Hedgehog signaling
Falkenstein, K. N., & Vokes, S. A. (2014) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2014.05.010 · Cited by 59 · see citing works
TIMP3: a physiological regulator of adult myogenesis
Liu, H., Chen, S., Jin, B., Carson, J. A., Niu, A., Durham, W., Lai, J.-Y., & Li, Y.-P. (2010) · Journal of Cell Science · doi:10.1242/jcs.057620 · Cited by 58 · see citing works
OCCURRENCE OF CENTRIOLES DURING SKELETAL AND CARDIAC MYOGENESIS
Przybylski, R. J. (1971) · The Journal of Cell Biology · doi:10.1083/jcb.49.1.214 · Cited by 56 · see citing works
Sonic Hedgehog-responsive Genes in the Fetal Prostate
Yu, M., Gipp, J. J., Yoon, J. W., Iannaccone, P., Walterhouse, D. O., & BUSHMAN, W. A. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m809172200 · Cited by 54 · see citing works
McDonald, A. A., Hebert, S. L., Kunz, M. D., Ralles, S. J., & McLoon, L. K. (2015) · Physiological Reports · doi:10.14814/phy2.12391 · Cited by 54 · see citing works
Desert Hedgehog Promotes Ischemia-Induced Angiogenesis by Ensuring Peripheral Nerve Survival
Renault, M., Chapouly, C., Yao, Q., Larrieu-Lahargue, F., Vandierdonck, S., Reynaud, A., Petit, M., Jaspard‐Vinassa, B., Belloc, I., Traiffort, É., et al. (2013) · Circulation Research · doi:10.1161/circresaha.113.300871 · Cited by 50 · see citing works
Gelatinase A (MMP-2) promotes murine adipogenesis
Bauters, D., Scroyen, I., Hul, M. V., & LIJNEN, H. R. (2015) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2015.04.003 · Cited by 47 · see citing works
Bernot, D., Barruet, E., Poggi, M., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.078444 · Cited by 46 · see citing works
Sonic Hedgehog Therapy in a Mouse Model of Age-Associated Impairment of Skeletal Muscle Regeneration
Piccioni, A., Gaetani, E., Neri, V., Gatto, I., Palladino, M., Silver, M., Smith, R. C., Giarretta, I., Pola, E., Hlatky, L., et al. (2013) · The Journals of Gerontology Series A · doi:10.1093/gerona/glt076 · Cited by 40 · see citing works
Piccioni, A., Gaetani, E., Palladino, M., Gatto, I., Smith, R. C., Neri, V., Marcantoni, M., Giarretta, I., Silver, M., Straino, S., et al. (2014) · Gene Therapy · doi:10.1038/gt.2014.13 · Cited by 39 · see citing works
Nakajima, H., Ito, M., Smookler, D. S., Shibata, F., Fukuchi, Y., Morikawa, Y., Ikeda, Y., Arai, F., Suda, T., Khokha, R., et al. (2010) · Blood · doi:10.1182/blood-2010-01-266528 · Cited by 33 · see citing works
Valin, A., Barnay‐Verdier, S., Robert, T., Ripoche, H., Brellier, F., Chevallier, O., Avril, M., & Magnaldo, T. (2009) · PLoS ONE · doi:10.1371/journal.pone.0004818 · Cited by 29 · see citing works
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- Authors
- Kopinke, D., Roberson, E. C., & Reiter, J. F.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Reiter, Jeremy F.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-07
- Volume
- 170
- Issue
- 2
- Pages
- 340-351.e12
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5617351
- OpenAlex
- W2735513135
- Cited by
- 260
- References
- 59
- Citations by year
- 2026: 34 · 2025: 33 · 2024: 24 · 2023: 32 · 2022: 27 · 2021: 32 · 2020: 33 · 2019: 24 · 2018: 16 · 2017: 4
- FWCI
- 8.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- NIH (AR054396, GM095941)
- Burroughs Wellcome Fund
- Packard Foundation
- ARCS Foundation
- Muscular Dystrophy Association (MDA294976)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
- Keywords
- primary cilia, fibro-adipogenic progenitors, skeletal muscle injury, adipogenesis, Duchenne muscular dystrophy, muscle regeneration, steatosis, TIMP-3, MMP-14, muscle fiber size
- MeSH terms
- Animals, Cilia, Regeneration, Stem Cells, Signal Transduction, Dystrophin, Adipocytes, Muscle, Skeletal, Tissue Inhibitor of Metalloproteinase-3, Muscular Dystrophy, Duchenne, Muscle Development, Adipogenesis, Mice, Matrix Metalloproteinase 14, Hedgehog Proteins
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