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Signaling through the insulin receptor governs central physiological functions related to cell growth and metabolism. Here we show by tandem native protein complex purification approach and super-resolution STED microscopy that insulin receptor activity requires association with the fundamental structural module in muscle, the dystrophin glycoprotein complex (DGC), and the desmosomal component plakoglobin (γ-catenin). The integrity of this high-molecular-mass assembly renders skeletal muscle susceptibility to insulin, because DGC-insulin receptor dissociation by plakoglobin downregulation reduces insulin signaling and causes atrophy. Furthermore, low insulin receptor activity in muscles from transgenic or fasted mice decreases plakoglobin-DGC-insulin receptor content on the plasma membrane, but not when plakoglobin is overexpressed. By masking β-dystroglycan LIR domains, plakoglobin prevents autophagic clearance of plakoglobin-DGC-insulin receptor co-assemblies and maintains their function. Our findings establish DGC as a signaling hub, and provide a possible mechanism for the insulin resistance in Duchenne Muscular Dystrophy, and for the cardiomyopathies seen with plakoglobin mutations. Insulin receptor signaling governs central physiological functions related to cell growth and metabolism. Here the authors use protein complex purification and super-resolution microscopy to show that insulin receptor activity requires association with dystrophin glycoprotein complex and plakoglobin.

The adult mammalian heart is non-regenerative owing to the post-mitotic nature of cardiomyocytes. The neonatal mouse heart can regenerate, but only during the first week of life. Here we show that changes in the composition of the extracellular matrix during this week can affect cardiomyocyte growth and differentiation in mice. We identify agrin, a component of neonatal extracellular matrix, as required for the full regenerative capacity of neonatal mouse hearts. In vitro , recombinant agrin promotes the division of cardiomyocytes that are derived from mouse and human induced pluripotent stem cells through a mechanism that involves the disassembly of the dystrophin–glycoprotein complex, and Yap- and ERK-mediated signalling. In vivo , a single administration of agrin promotes cardiac regeneration in adult mice after myocardial infarction, although the degree of cardiomyocyte proliferation observed in this model suggests that there are additional therapeutic mechanisms. Together, our results uncover a new inducer of mammalian heart regeneration and highlight fundamental roles of the extracellular matrix in cardiac repair. The extracellular matrix protein agrin promotes cardiac regeneration in adult mice after myocardial infarction; it modulates cardiac differentiation and proliferation by interacting with the dystrophin–glycoprotein complex, Yap and ERK-mediated signalling. Born Agrin mouse hearts The neonatal mouse heart can regenerate during a limited time period after birth, but this property is rapidly lost. Eldad Tzahor and colleagues identify a component of the neonatal heart extracellular matrix, agrin, which is required for heart regeneration in neonatal mice. They further show that recombinant agrin can be used to improve the function of adult mouse hearts after myocardial infarction. The mechanism by which agrin can promote heart function and regeneration may be multi-faceted, but the authors also show that it can boost cardiomyocyte proliferation, which could contribute to the observed effects.

Signaling through the insulin receptor governs central physiological functions related to cell growth and metabolism. Here we show by tandem native protein complex purification approach and super-resolution STED microscopy that insulin receptor activity requires association with the fundamental structural module in muscle, the dystrophin glycoprotein complex (DGC), and the desmosomal component plakoglobin (gamma-catenin). The integrity of this high-molecular-mass assembly renders skeletal muscle susceptibility to insulin because DGC-insulin receptor dissociation by plakoglobin downregulation reduced insulin signaling and caused atrophy. Furthermore, impaired insulin receptor function in muscles from diabetic mice reduced plakoglobin-DGC-insulin receptor content on the plasma membrane; however, plakoglobin overexpression alone restored DGC association with the insulin receptor, and stimulated glucose uptake. Our findings establish DGC as a signaling hub, containing plakoglobin as an auxiliary subunit, and provide a possible mechanism for the insulin resistance in Duchenne Muscular Dystrophy, and for the cardiomyopathies seen with plakoglobin mutations.

PI3K-Akt-FoxO-mTOR signaling is the central pathway controlling growth and metabolism in all cells. Activation of this pathway requires ubiquitination of Akt prior to its activation by phosphorylation. Here, we found that the deubiquitinating (DUB) enzyme USP1 removes K63-linked polyubiquitin chains on Akt to sustain PI3K-Akt-FoxO signaling low during prolonged starvation. DUB screening platform identified USP1 as a direct DUB for Akt, and USP1 depletion in atrophying muscle increased Akt ubiquitination, PI3K-Akt-FoxO signaling, and glucose uptake during fasting. Co-immunoprecipitation and mass spectrometry identified Disabled-2 (Dab2) and the tuberous sclerosis complex TSC1/TSC2 as USP1 bound proteins. During starvation, Dab2 was essential for Akt recruitment to USP1/UAF1 complex, and for PI3K-Akt-FoxO inhibition. Additionally, to maintain its own protein levels high, USP1 limits TSC1 levels to sustain mTOR-mediated basal protein synthesis rates. This USP1-mediated suppression of PI3K-Akt-FoxO signaling probably contributes to insulin resistance in catabolic diseases and perhaps to malignancies seen with USP1 mutations.