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Excess muscle plasma membrane leak disrupts extracellular matrix content and shifts macrophage-mediated muscle repair [scRNA-Seq]

ABSTRACT: Plasma membrane repair is critical for tissue integrity, especially for elongated contractile muscle cells. Genetically-mediated defects in plasma membrane resealing produce persistent leak, leading to a disordered extracellular matrix. Loss of the membrane repair protein dysferlin slows sarcolemmal resealing and promotes excess leak. Annexin A6 is also implicated in sarcolemmal repair, forming repair caps at the site of membrane disruption. On its own, deletion of the gene for annexin A6, Anxa6, had little effect on muscle health. In contrast, combined loss of dysferlin and annexin A6 (DysfA6) generated muscle fibers with profoundly defective membrane leak. Strikingly, Anxa6 deletion in the context of loss of dystrophin (mdxA6) did not exacerbate muscle defects. The persistent membrane leak in DysfA6 muscle resulted in marked macrophage infiltration with disordered macrophage polarization. Injured muscle fibers were targets of macrophage efferocytosis. Loss of Anxa6 was associated with increased expression of annexins A1 and A2, both of which were heavily deposited into the extracellular matrix. In vitro, macrophages exposed to annexins A1 and A2 expressed increased Csf1, consistent with a model where excess leak results in annexins A1 and A2 in the extracellular matrix, where this protein composition elicits macrophage proliferation and efferocytosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE328601 | GEO | 2026/06/15

REPOSITORIES: GEO

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Excess muscle plasma membrane leak disrupts extracellular matrix content and shifts macrophage-mediated muscle repair

Project description:Plasma membrane repair is critical for tissue integrity, especially for elongated contractile muscle cells. Genetically-mediated defects in plasma membrane resealing produce persistent leak, leading to a disordered extracellular matrix. Loss of the membrane repair protein dysferlin slows sarcolemmal resealing and promotes excess leak. Annexin A6 is also implicated in sarcolemmal repair, forming repair caps at the site of membrane disruption. On its own, deletion of the gene for annexin A6, Anxa6, had little effect on muscle health. In contrast, combined loss of dysferlin and annexin A6 (DysfA6) generated muscle fibers with profoundly defective membrane leak. Strikingly, Anxa6 deletion in the context of loss of dystrophin (mdxA6) did not exacerbate muscle defects. The persistent membrane leak in DysfA6 muscle resulted in marked macrophage infiltration with disordered macrophage polarization. Injured muscle fibers were targets of macrophage efferocytosis. Loss of Anxa6 was associated with increased expression of annexins A1 and A2, both of which were heavily deposited into the extracellular matrix. In vitro, macrophages exposed to annexins A1 and A2 expressed increased Csf1, consistent with a model where excess leak results in annexins A1 and A2 in the extracellular matrix, where this protein composition elicits macrophage proliferation and efferocytosis.

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Excess muscle plasma membrane leak disrupts extracellular matrix content and shifts macrophage-mediated muscle repair

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Annexin A6-mediated tumor suppression requires inhibition of calcium influx and down-regulation of the calcium-activated RasGRF2

Project description:Membrane association of the tumor suppressor, annexin A6 (AnxA6), has been shown to regulate plasma membrane permeability to extracellular Ca2+, inhibit anchorage-independent tumor cell growth and paradoxically, promote tumor cell motility by mechanisms that remains poorly understood. Here, we identified RasGRF2, a Ca2+-activated Ras-specific guanine nucleotide exchange factor, as a major effector of AnxA6-elicited tumor-associated phenotypes in breast cancer cells. We demonstrate that reduced expression or loss of AnxA6 in breast cancer cells is associated with up-regulation of RasGRF2, increased Ras activity and consequently, early onset and rapid growth of xenograft tumors. Meanwhile, up-regulation of AnxA6 in AnxA6-low breast cancer cells is associated with a decrease in Ras activity and growth of xenograft tumors but on the contrary, an increase in Cdc42 activity and EGF-stimulated cell motility. Inhibition of Ca2+ influx into AnxA6-low breast cancer cells via Ni2+-sensitive or non-selective Ca2+ channels dose-dependently suppressed the expression of RasGRF2, induced the expression of AnxA6 and consequently, inhibited tumor cell proliferation. Finally, aberrant expression of RasGRF2 may be triggered by AnxA6-mediated or pharmacological inhibition of non-selective Ca2+ channels and occurs at least in part, by promoter methylation. These data for the first time identify RasGRF2 as a major effector of AnxA6-dependent breast tumor growth and motility and that regulated Ca2+ influx and/or RasGRF2 may be potential therapeutic targets for rapidly growing AnxA6-low breast carcinomas

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Role of annexin A2 in muscle repair

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| PRJNA345192 | ENA

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