Annexin A2 links poor myofiber repair with inflammation and adipogenic replacement of the injured muscle

Defour, Aurélia; Medikayala, Sushma; Meulen, Jan van der; Hogarth, Marshall W.; Holdreith, Nicholas; Malatras, Apostolos; Duddy, William; Boehler, J; Nagaraju, Kanneboyina; Jaiswal, Jyoti K.

doi:10.1093/hmg/ddx065

Cited by 49 publications

(61 citation statements)

References 65 publications

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“…• Leakage of damage-associated molecules such as annexin A2 from dysferlin-deficient myofibers [211] through sarcolemma lesions [210], • Intrinsic pro-inflammatory signaling of dysferlin-deficient muscle fibers [118,212], •…”

Section: Inflammatory Processesmentioning

confidence: 99%

Functions of Vertebrate Ferlins

Bulankina

Thoms

2020

Cells

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Ferlins are multiple-C2-domain proteins involved in Ca2+-triggered membrane dynamics within the secretory, endocytic and lysosomal pathways. In bony vertebrates there are six ferlin genes encoding, in humans, dysferlin, otoferlin, myoferlin, Fer1L5 and 6 and the long noncoding RNA Fer1L4. Mutations in DYSF (dysferlin) can cause a range of muscle diseases with various clinical manifestations collectively known as dysferlinopathies, including limb-girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy. A mutation in MYOF (myoferlin) was linked to a muscular dystrophy accompanied by cardiomyopathy. Mutations in OTOF (otoferlin) can be the cause of nonsyndromic deafness DFNB9. Dysregulated expression of any human ferlin may be associated with development of cancer. This review provides a detailed description of functions of the vertebrate ferlins with a focus on muscle ferlins and discusses the mechanisms leading to disease development.

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Section: Inflammatory Processesmentioning

confidence: 99%

Functions of Vertebrate Ferlins

Bulankina

Thoms

2020

Cells

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“…It is also worth noting that there were significant differences in the pre-TBI baseline levels in the grip and the Rotor Rod tests between WT and A2KO sham groups. The poorer performance of motor function in A2KO mice was speculated upon by a recent study, which reported that A2KO mice had a mild but progressive muscle weakness in locomotor activity [21]. Therefore, the decline of muscle strength or the worse locomotor activity of A2KO mice might also contribute to the worse sensorimotor function deficits after TBI.…”

Section: Discussionmentioning

confidence: 98%

Annexin A2 Deficiency Exacerbates Neuroinflammation and Long-Term Neurological Deficits after Traumatic Brain Injury in Mice

Liu

Jiang

Chung

et al. 2019

IJMS

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Our laboratory and others previously showed that Annexin A2 knockout (A2KO) mice had impaired blood–brain barrier (BBB) development and elevated pro-inflammatory response in macrophages, implying that Annexin A2 (AnxA2) might be one of the key endogenous factors for maintaining homeostasis of the neurovascular unit in the brain. Traumatic brain injury (TBI) is an important cause of disability and mortality worldwide, and neurovascular inflammation plays an important role in the TBI pathophysiology. In the present study, we aimed to test the hypothesis that A2KO promotes pro-inflammatory response in the brain and worsens neurobehavioral outcomes after TBI. TBI was conducted by a controlled cortical impact (CCI) device in mice. Our experimental results showed AnxA2 expression was significantly up-regulated in response to TBI at day three post-TBI. We also found more production of pro-inflammatory cytokines in the A2KO mouse brain, while there was a significant increase of inflammatory adhesion molecules mRNA expression in isolated cerebral micro-vessels of A2KO mice compared with wild-type (WT) mice. Consistently, the A2KO mice brains had a significant increase in leukocyte brain infiltration at two days after TBI. Importantly, A2KO mice had significantly worse sensorimotor and cognitive function deficits up to 28 days after TBI and significantly larger brain tissue loss. Therefore, these results suggested that AnxA2 deficiency results in exacerbated early neurovascular pro-inflammation, which leads to a worse long-term neurologic outcome after TBI.

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“…The presence of dysferlin in vesicles or other membranous organelles seems to be important for such functions [5]. Annexin A2 is also critical for plasmalemma repair [4,49], and its ablation causes progressive muscle weakening [49]. Interplay between dysferlin, annexin A2, and actin remodeling has been observed during plasmalemmal repair.…”

Section: Discussionmentioning

confidence: 99%

Defects in G-Actin Incorporation into Filaments in Myoblasts Derived from Dysferlinopathy Patients Are Restored by Dysferlin C2 Domains

Báez‐Matus

Figueroa-Cares

González‐Jamett

et al. 2019

IJMS

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Dysferlin is a transmembrane C-2 domain-containing protein involved in vesicle trafficking and membrane remodeling in skeletal muscle cells. However, the mechanism by which dysferlin regulates these cellular processes remains unclear. Since actin dynamics is critical for vesicle trafficking and membrane remodeling, we studied the role of dysferlin in Ca2+-induced G-actin incorporation into filaments in four different immortalized myoblast cell lines (DYSF2, DYSF3, AB320, and ER) derived from patients harboring mutations in the dysferlin gene. As compared with immortalized myoblasts obtained from a control subject, dysferlin expression and G-actin incorporation were significantly decreased in myoblasts from dysferlinopathy patients. Stable knockdown of dysferlin with specific shRNA in control myoblasts also significantly reduced G-actin incorporation. The impaired G-actin incorporation was restored by the expression of full-length dysferlin as well as dysferlin N-terminal or C-terminal regions, both of which contain three C2 domains. DYSF3 myoblasts also exhibited altered distribution of annexin A2, a dysferlin partner involved in actin remodeling. However, dysferlin N-terminal and C-terminal regions appeared to not fully restore such annexin A2 mislocation. Then, our results suggest that dysferlin regulates actin remodeling by a mechanism that does to not involve annexin A2.

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Annexin A2 links poor myofiber repair with inflammation and adipogenic replacement of the injured muscle

Cited by 49 publications

References 65 publications

Functions of Vertebrate Ferlins

Functions of Vertebrate Ferlins

Annexin A2 Deficiency Exacerbates Neuroinflammation and Long-Term Neurological Deficits after Traumatic Brain Injury in Mice

Defects in G-Actin Incorporation into Filaments in Myoblasts Derived from Dysferlinopathy Patients Are Restored by Dysferlin C2 Domains

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