Abstract
Muscle cell plasma membrane is frequently damaged by mechanical activity, and its repair requires the membrane protein dysferlin. We previously identified that, similar to dysferlin deficit, lack of annexin A2 (AnxA2) also impairs repair of skeletal myofibers. Here, we have studied the mechanism of AnxA2-mediated muscle cell membrane repair in cultured muscle cells. We find that injury-triggered increase in cytosolic calcium causes AnxA2 to bind dysferlin and accumulate on dysferlin-containing vesicles as well as with dysferlin at the site of membrane injury. AnxA2 accumulates on the injured plasma membrane in cholesterol-rich lipid microdomains and requires Src kinase activity and the presence of cholesterol. Lack of AnxA2 and its failure to translocate to the plasma membrane, both prevent calcium-triggered dysferlin translocation to the plasma membrane and compromise repair of the injured plasma membrane. Our studies identify that Anx2 senses calcium increase and injury-triggered change in plasma membrane cholesterol to facilitate dysferlin delivery and repair of the injured plasma membrane.
Highlights
Mechanical strain associated with muscle contraction routinely damages the myofiber plasma membrane (PM) [1]
As injury-triggered calcium influx is a major stimulus for annexin response to PM injury, we examined injury-triggered and Ca2+ -dependent PM translocation annexin A2 (AnxA2) in the muscle cell
Confocal microscopy of myoblasts expressing GFP-tagged AnxA2 showed that within seconds of injury, AnxA2 accumulates at the site of PM injury (Figure 1A,B and Video S1)
Summary
Mechanical strain associated with muscle contraction routinely damages the myofiber plasma membrane (PM) [1]. PM injury, myofibers need to efficiently repair these injuries [2] This is achieved with the help of the muscle membrane protein dysferlin, mutations in which impair myofiber repair leading to muscle degeneration [3,4,5]. Ferlin proteins are similar to the C2 domain-containing proteins such as synaptotagmins, which facilitate Ca2+ -triggered vesicle fusion [6,7]. Dysferlin is implicated in facilitating injury-triggered membrane fusion to enable plasma membrane repair (PMR) [8]. Prior studies show that dysferlin and associated PMR proteins accumulate at the site of sarcolemma damage in mature myofibers [10,11]. Using dysferlin deficient mouse myofibers and patient myoblasts, we have identified that dysferlin helps tether
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