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Review
. 2021 May 17;22(10):5276.
doi: 10.3390/ijms22105276.

Annexins and Membrane Repair Dysfunctions in Muscular Dystrophies

Coralie Croissant  1 , Romain Carmeille  1 , Charlotte Brévart  1 , Anthony Bouter  1
Affiliations
Review

Annexins and Membrane Repair Dysfunctions in Muscular Dystrophies

Coralie Croissant et al. Int J Mol Sci. .

Abstract

Muscular dystrophies constitute a group of genetic disorders that cause weakness and progressive loss of skeletal muscle mass. Among them, Miyoshi muscular dystrophy 1 (MMD1), limb girdle muscular dystrophy type R2 (LGMDR2/2B), and LGMDR12 (2L) are characterized by mutation in gene encoding key membrane-repair protein, which leads to severe dysfunctions in sarcolemma repair. Cell membrane disruption is a physiological event induced by mechanical stress, such as muscle contraction and stretching. Like many eukaryotic cells, muscle fibers possess a protein machinery ensuring fast resealing of damaged plasma membrane. Members of the annexins A (ANXA) family belong to this protein machinery. ANXA are small soluble proteins, twelve in number in humans, which share the property of binding to membranes exposing negatively-charged phospholipids in the presence of calcium (Ca2+). Many ANXA have been reported to participate in membrane repair of varied cell types and species, including human skeletal muscle cells in which they may play a collective role in protection and repair of the sarcolemma. Here, we discuss the participation of ANXA in membrane repair of healthy skeletal muscle cells and how dysregulation of ANXA expression may impact the clinical severity of muscular dystrophies.

Keywords: DMD; FSHD; LGMD; annexins; genetic modifiers; membrane repair; muscular dystrophy; skeletal muscle.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
Scheme of skeletal muscle and associated structures. (Left-hand part) Epimysium, perimysium, and endomysium constitute three connective tissue layers that form the lattice network and associated basement membranes in which myofibers regenerate after injury. The epimysium is the outer layer that surrounds the entire muscle and is contiguous with the tendon and endosteum (fascia surrounding bone). The perimysium surrounds bundles of myofibers. The endomysium is located between individual muscle fibers. (Right-hand part) Satellite cells are located between basement membrane and sarcolemma. Sarcolemma bounds each myofiber, which is composed by multiple nuclei and the sarcoplasm that contains mitochondria, sarcoplasmic reticulum and myofibrils. The myofibril is the contractile unit of a myofiber. Specialized cytoskeleton within the myofibril forms repeated structures, called sarcomeres, which appear as a succession of light and dark bands under polarized light optical microscopy. The sarcoplasmic reticulum is the major provider of Ca2+ required for muscle contraction. It is connected to transverse tubules that surround sarcomeres. Adapted from Reference [15] with the Permission 5036470714502 from John Wiley and sons.
Figure 2
Figure 2
“Lipid patch” repair mechanism. (A) In the “lipid patch” model, the micrometer-sized rupture of the plasma membrane is followed by a massive entry of Ca2+ into the damaged cell. (B) The local increase in intracellular Ca2+ concentration initiates the recruitment of intracellular vesicles and (C) their fusion to form a vesicular aggregate or “patch”. The “patch” fuses at the ruptured area and plugs the lesion, which stops the mixing of extracellular and intracellular compartments.
Figure 3
Figure 3
The sarcolemma repair machinery. (A) In normal, intact myofibers, full-length DYSF is localized at the sarcolemma where it interacts with ANXA1 and ANXA2. ANXA2 may also interact with CAV3. MG53 is mostly tethered to the sarcolemma. All other components of the membrane repair machinery may be soluble in the sarcoplasm. ANXA1 and A2 exist as both monomeric and heterotetrameric forms with their binding partners S100A10 (for ANXA2) and S100A11 (for ANXA1). (B) A disruption of the sarcolemma results in the influx of Ca2+ and oxidized milieu into the sarcoplasm that activates (1) the recruitment of ANXA5 and MG53 to the edges of the torn membrane that form arrays, which stabilize and prevent the expansion of the rupture, (2) the formation of the “lipid patch” through interaction of ANXA1 and ANXA2 -covered vesicles, (3) generation of mini-dysferlinec72 and the recruitment of mini-dysferlinec72-covered vesicles, that ensures hanging of the patch to the damaged sarcolemma, and (4) the recruitment of ANXA6 at the disruption site that may induce folding and curvature of the sarcolemma, which promote the formation of a tight membrane structure, i.e., the repair cap subdomain. Adapted from [24,26,40,41,46,55,70].
Figure 4
Figure 4
Structure of ANX. (A) Schematic representation of ANX. The four repeat sequences of the core domain fold into a curved-shape disk. The convex face binds Ca2+ (blue spheres) and interacts with membrane. The N-terminal domain varies between ANX and regulates their function by interacting with other proteins. (B) Representation of the tertiary structure of ANX. Image of 1AVH (human ANXA5) [103] created with MMDB [104]. (C) Schematic representation of molecular interactions between ANX, Ca2+, and membrane.
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