Fibroadipogenic Progenitors Are Responsible for Muscle Loss in Limb Girdle Muscular Dystrophy 2B

Overview

Journal Nat Commun

Specialty Biology

Date 2019 Jun 5

PMID 31160583

Citations 86

Authors

Marshall W Hogarth

Aurelia Defour

Christopher Lazarski

Eduard Gallardo

Jordi Diaz Manera

Terence A Partridge

Kanneboyina Nagaraju

Jyoti K Jaiswal

Affiliations

Soon will be listed here.

Abstract

Muscle loss due to fibrotic or adipogenic replacement of myofibers is common in muscle diseases and muscle-resident fibro/adipogenic precursors (FAPs) are implicated in this process. While FAP-mediated muscle fibrosis is widely studied in muscle diseases, the role of FAPs in adipogenic muscle loss is not well understood. Adipogenic muscle loss is a feature of limb girdle muscular dystrophy 2B (LGMD2B) - a disease caused by mutations in dysferlin. Here we show that FAPs cause the adipogenic loss of dysferlin deficient muscle. Progressive accumulation of Annexin A2 (AnxA2) in the myofiber matrix causes FAP differentiation into adipocytes. Lack of AnxA2 prevents FAP adipogenesis, protecting against adipogenic loss of dysferlinopathic muscle while exogenous AnxA2 enhances muscle loss. Pharmacological inhibition of FAP adipogenesis arrests adipogenic replacement and degeneration of dysferlin-deficient muscle. These results demonstrate the pathogenic role of FAPs in LGMD2B and establish these cells as therapeutic targets to ameliorate muscle loss in patients.

Citing Articles

Metabolic dysregulation contributes to the development of dysferlinopathy.

Furrer R, Dilbaz S, Steurer S, Santos G, Karrer-Cardel B, Ritz D Life Sci Alliance. 2025; 8(5).

PMID: 40021220 PMC: 11871293. DOI: 10.26508/lsa.202402991.

Single-Nucleus RNA Sequencing Reveals Cellular Transcriptome Features at Different Growth Stages in Porcine Skeletal Muscle.

Chen Z, Wu X, Zheng D, Wang Y, Chai J, Zhang T Cells. 2025; 14(1.

PMID: 39791738 PMC: 11720419. DOI: 10.3390/cells14010037.

Sarcopenia and cachexia: molecular mechanisms and therapeutic interventions.

Wang T, Zhou D, Hong Z MedComm (2020). 2025; 6(1):e70030.

PMID: 39764565 PMC: 11702502. DOI: 10.1002/mco2.70030.

Pdgfrα stromal cells, a key regulator for tissue homeostasis and dysfunction in distinct organs.

Kang X, Zhao K, Huang Z, Fukada S, Qi X, Miao H Genes Dis. 2025; 12(2):101264.

PMID: 39759120 PMC: 11696774. DOI: 10.1016/j.gendis.2024.101264.

Tenascin-C from the tissue microenvironment promotes muscle stem cell self-renewal through Annexin A2.

Loreti M, Cecchini A, Kaufman C, Stamenkovic C, Renero A, Nicoletti C bioRxiv. 2024; .

PMID: 39554125 PMC: 11565721. DOI: 10.1101/2024.10.29.620732.

References

Chavey C, Mari B, Monthouel M, Bonnafous S, Anglard P, Van Obberghen E . Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation. J Biol Chem. 2003; 278(14):11888-96. DOI: 10.1074/jbc.M209196200. View

Swisher J, Burton N, Bacot S, Vogel S, Feldman G . Annexin A2 tetramer activates human and murine macrophages through TLR4. Blood. 2009; 115(3):549-58. PMC: 2810992. DOI: 10.1182/blood-2009-06-226944. View

Kasai T, Nakatani M, Ishiguro N, Ohno K, Yamamoto N, Morita M . Promethazine Hydrochloride Inhibits Ectopic Fat Cell Formation in Skeletal Muscle. Am J Pathol. 2017; 187(12):2627-2634. DOI: 10.1016/j.ajpath.2017.08.008. View

Dong Y, Silva K, Dong Y, Zhang L . Glucocorticoids increase adipocytes in muscle by affecting IL-4 regulated FAP activity. FASEB J. 2014; 28(9):4123-32. PMC: 4139907. DOI: 10.1096/fj.14-254011. View

Millay D, Maillet M, Roche J, Sargent M, McNally E, Bloch R . Genetic manipulation of dysferlin expression in skeletal muscle: novel insights into muscular dystrophy. Am J Pathol. 2009; 175(5):1817-23. PMC: 2774048. DOI: 10.2353/ajpath.2009.090107. View

Nagy N, Nonneman R, Llanga T, Dial C, Riddick N, Hampton T . Hip region muscular dystrophy and emergence of motor deficits in dysferlin-deficient Bla/J mice. Physiol Rep. 2017; 5(6). PMC: 5371557. DOI: 10.14814/phy2.13173. View

Liu J, Aoki M, Illa I, Wu C, Fardeau M, Angelini C . Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy. Nat Genet. 1998; 20(1):31-6. DOI: 10.1038/1682. View

Lo H, Cooper S, Evesson F, Seto J, Chiotis M, Tay V . Limb-girdle muscular dystrophy: diagnostic evaluation, frequency and clues to pathogenesis. Neuromuscul Disord. 2007; 18(1):34-44. DOI: 10.1016/j.nmd.2007.08.009. View

Orimo S, Hiyamuta E, Arahata K, Sugita H . Analysis of inflammatory cells and complement C3 in bupivacaine-induced myonecrosis. Muscle Nerve. 1991; 14(6):515-20. DOI: 10.1002/mus.880140605. View

10.

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

11.

Angelini C, Peterle E, Gaiani A, Bortolussi L, Borsato C . Dysferlinopathy course and sportive activity: clues for possible treatment. Acta Myol. 2011; 30(2):127-32. PMC: 3235880. View

12.

Zhao P, Seo J, Wang Z, Wang Y, Shneiderman B, Hoffman E . In vivo filtering of in vitro expression data reveals MyoD targets. C R Biol. 2004; 326(10-11):1049-65. DOI: 10.1016/j.crvi.2003.09.035. View

13.

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

14.

Lennon N, Kho A, Bacskai B, Perlmutter S, Hyman B, Brown Jr R . Dysferlin interacts with annexins A1 and A2 and mediates sarcolemmal wound-healing. J Biol Chem. 2003; 278(50):50466-73. DOI: 10.1074/jbc.M307247200. View

15.

Cagliani R, Magri F, Toscano A, Merlini L, Fortunato F, Lamperti C . Mutation finding in patients with dysferlin deficiency and role of the dysferlin interacting proteins annexin A1 and A2 in muscular dystrophies. Hum Mutat. 2005; 26(3):283. DOI: 10.1002/humu.9364. View

16.

Mueller A, van Velthoven C, Fukumoto K, Cheung T, Rando T . Intronic polyadenylation of PDGFRα in resident stem cells attenuates muscle fibrosis. Nature. 2016; 540(7632):276-279. PMC: 5384334. DOI: 10.1038/nature20160. View

17.

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

18.

Kumar A, Bhatnagar S, Kumar A . Matrix metalloproteinase inhibitor batimastat alleviates pathology and improves skeletal muscle function in dystrophin-deficient mdx mice. Am J Pathol. 2010; 177(1):248-60. PMC: 2893668. DOI: 10.2353/ajpath.2010.091176. View

19.

Cohen T, Cohen J, Partridge T . Myogenesis in dysferlin-deficient myoblasts is inhibited by an intrinsic inflammatory response. Neuromuscul Disord. 2012; 22(7):648-58. PMC: 4147957. DOI: 10.1016/j.nmd.2012.03.002. View

20.

Jaiswal J, Lauritzen S, Scheffer L, Sakaguchi M, Bunkenborg J, Simon S . S100A11 is required for efficient plasma membrane repair and survival of invasive cancer cells. Nat Commun. 2014; 5:3795. PMC: 4026250. DOI: 10.1038/ncomms4795. View