Annexin A2 links poor myofiber repair with inflammation and adipogenic replacement of the injured muscle.
Repair of skeletal muscle after sarcolemmal damage involves dysferlin and dysferlin-interacting proteins such as annexins. Mice and patient lacking dysferlin exhibit chronic muscle inflammation and adipogenic replacement of the myofibers. Here, we show that similar to dysferlin, lack of annexin A2 (AnxA2) also results in poor myofiber repair and progressive muscle weakening with age. By longitudinal analysis of AnxA2-deficient muscle we find that poor myofiber repair due to the lack of AnxA2 does not result in chronic inflammation or adipogenic replacement of the myofibers. Further, deletion of AnxA2 in dysferlin deficient mice reduced muscle inflammation, adipogenic replacement of myofibers, and improved muscle function. These results identify multiple roles of AnxA2 in muscle repair, which includes facilitating myofiber repair, chronic muscle inflammation and adipogenic replacement of dysferlinopathic muscle. It also identifies inhibition of AnxA2-mediated inflammation as a novel therapeutic avenue for treating muscle loss in dysferlinopathy.
Center for Genetic Medicine Research, Children's National Health System, Washington, DC 20010, USA.
Aurelia
A
Defour
Center for Genetic Medicine Research, Children's National Health System, Washington, DC 20010, USA.
Sushma
S
Medikayala
Center for Genetic Medicine Research, Children's National Health System, Washington, DC 20010, USA.
Jack H
JH
Van der Meulen
Center for Genetic Medicine Research, Children's National Health System, Washington, DC 20010, USA.
Marshall W
MW
Hogarth
Center for Genetic Medicine Research, Children's National Health System, Washington, DC 20010, USA.
Nicholas
N
Holdreith
Center for Research in Myology 75013, Sorbonne Universités, UPMC University Paris 06, INSERM UMRS975, CNRS FRE3617, GH Pitié Salpêtrière, Paris 13, Paris, France.
Apostolos
A
Malatras
Center for Research in Myology 75013, Sorbonne Universités, UPMC University Paris 06, INSERM UMRS975, CNRS FRE3617, GH Pitié Salpêtrière, Paris 13, Paris, France.|Northern Ireland Centre for Stratified Medicine, Altnagelvin Hospital Campus, Ulster University, Londonderry, Northern Ireland, BT52 1SJ UK.
William
W
Duddy
Center for Genetic Medicine Research, Children's National Health System, Washington, DC 20010, USA.
Jessica
J
Boehler
Center for Genetic Medicine Research, Children's National Health System, Washington, DC 20010, USA.|Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, 20052 USA.
Kanneboyina
K
Nagaraju
Center for Genetic Medicine Research, Children's National Health System, Washington, DC 20010, USA.|Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, 20052 USA.
Jyoti K
JK
Jaiswal
D050156:Adipogenesis; D000818:Animals; D017306:Annexin A2 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D000073939:Dysferlin; D007249:Inflammation / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism; D049288:Muscular Dystrophies, Limb-Girdle / Q000378:metabolism / Q000628:therapy; D009210:Myofibrils / Q000502:physiology; D012508:Sarcolemma / Q000378:metabolism
D017306:Annexin A2; C497505:Dysf protein, mouse; D000073939:Dysferlin; D008565:Membrane Proteins