SWELL1 regulates skeletal muscle cell size, intracellular signaling, adiposity and glucose metabolism

Kumar, Ashutosh; Xie, Litao; Ta, Chau My; Hinton, Antentor; Gunasekar, Susheel K.; Minerath, Rachel A; Shen, Karen; Maurer, Joshua A.; Grueter, Chad E.; Abel, E. Dale; Meyer, Gretchen A.; Sah, Rajan

doi:10.7554/elife.58941

Cited by 48 publications

(57 citation statements)

References 69 publications

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“…Moreover, Lrrc8a mRNA is highly expressed in HUVECs relative to adipocyte and myotube cell lines examined previously (19,20), higher than many endothelial genes, and higher than other mechanosensitive (Piezo1) and mechanoresponsive (TRPV4) ion channels with wellestablished roles in endothelial biology (3,7,8,(80)(81)(82)(83)(84)(85)(86).…”

Section: Discussionmentioning

confidence: 85%

“…C, Expression levels of select LRRC8 mRNA, classic endothelial markers, and mechanoresponsive ion channels in shScr and shLrrc8a treated HUVECs. D, Expression levelsLRRC8a-e mRNA in HUVECs compared to data previously published from C2C12 myotubes(20) and differentiated 3T3-F442A adipocytes(19). For C, statistical significance between the indicated values were calculated using an unpaired two-tailed Student's t-test.…”

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confidence: 99%

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The SWELL1-LRRC8 complex regulates endothelial AKT-eNOS signaling and vascular function

Alghanem

Abello

Maurer

et al. 2021

eLife

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The endothelium responds to numerous chemical and mechanical factors in regulating vascular tone, blood pressure and blood flow. The endothelial volume regulatory anion channel (VRAC) has been proposed to be mechano-sensitive and thereby sense fluid flow and hydrostatic pressure to regulate vascular function. Here, we show that the Leucine Rich Repeat Containing Protein 8a, LRRC8A (SWELL1) is required for VRAC in human umbilical vein endothelial cells (HUVECs). Endothelial LRRC8A regulates AKT-eNOS signaling under basal, stretch and shear-flow stimulation, forms a GRB2-Cav1-eNOS signaling complex, and is required for endothelial cell alignment to laminar shear flow. Endothelium-restricted Lrrc8a KO mice develop hypertension in response to chronic angiotensin-II infusion and exhibit impaired retinal blood flow with both diffuse and focal blood vessel narrowing in the setting of Type 2 diabetes (T2D). These data demonstrate that LRRC8A regulates AKT-eNOS in endothelium and is required for maintaining vascular function, particularly in the setting of T2D.

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Section: Discussionmentioning

confidence: 85%

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confidence: 99%

The SWELL1-LRRC8 complex regulates endothelial AKT-eNOS signaling and vascular function

Alghanem

Abello

Maurer

et al. 2021

eLife

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“…Indeed, prior work highlights each of these modes of SWELL1-LRRC8 channel complex signaling. We showed previously SWELL1 to mediate insulin-PI3K-AKT signaling in adipocytes and skeletal muscle via non-conductive signaling mechanisms, and thereby regulates insulin-sensitivity, by modulating GRB2 signaling [24][25][26] . Also, we and others showed SWELL1-LRRC8 channel activity (conductive signaling) in the pancreatic b-cell is required for normal insulin secretion 27,28 .…”

Section: Swell1 or Lrrc8amentioning

confidence: 90%

“…As SWELL1 ablation markedly reduces insulin-pAKT2-pGSK3β signaling 24,26,41 and cellular glycogen content 24 , we asked whether the SN-401-mediated increase in SWELL1 would increase glucose incorporation into tissue glycogen in the setting of T2D. Indeed, liver, adipose, and skeletal muscle glucose incorporation into glycogen is markedly increased in SN-401treated mice ( Fig.…”

Section: Sn-401 Improves Systemic Insulin Sensitivity Tissue Glucosementioning

confidence: 99%

Small molecule SWELL1-LRRC8 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes

Sk¹,

Xie²,

et al. 2021

Preprint

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Type 2 diabetes (T2D) is associated with insulin resistance, impaired insulin secretion from the pancreatic β-cell, and nonalcoholic fatty liver disease (NAFLD). SWELL1 (LRRC8a) ablation impairs adipose and skeletal muscle insulin-pAKT2 signaling, β-cell insulin secretion and glycemic control - suggesting that SWELL1-LRRC8 complex dysfunction contributes to T2D pathogenesis. Here, we show that ICl,SWELL and SWELL1 protein are reduced in adipose and β-cells in murine and human T2D. Combining cryo-electron microscopy, molecular docking, medicinal chemistry, and functional studies, we define a structure activity relationship to rationally-designed active derivatives (SN-40X) of a SWELL1 channel inhibitor (DCPIB/SN-401), that bind the SWELL1-LRRC8 hexameric complex, restore SWELL1-LRRC8 protein, plasma membrane trafficking, signaling and islet insulin secretion via SWELL1-dependent mechanisms. In vivo, SN-401 and active SN-40X compounds restore glycemic control and prevents NAFLD by improving insulin-sensitivity and insulin secretion in murine T2D. These findings demonstrate that small molecule SWELL1 modulators restore SWELL1-dependent insulin-sensitivity and insulin secretion in T2D and may represent a first-in-class therapeutic approach for T2D and NAFLD.

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“…The first, SWELL1 (LRRC8A), is a component of the volume-regulated anion channel (VRAC), which is activated by cell swelling. It has been shown to participate in the regulation of myogenic differentiation and insulin-PI3K-AKT-AS160, ERK1/2, and mTOR signalling in myotubes via GRB2-mediated signalling and to be required for maintaining normal exercise capacity and muscle endurance [341]. It has yet to be investigated whether SWELL1 participates in the post-prandial muscle cell volume increase-associated anabolic response and its termination with the bag-full state.…”

Section: Muscle Volume Changes and Regulationmentioning

confidence: 99%

Interactions between Growth of Muscle and Stature: Mechanisms Involved and Their Nutritional Sensitivity to Dietary Protein: The Protein-Stat Revisited

Millward

2021

Nutrients

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Childhood growth and its sensitivity to dietary protein is reviewed within a Protein-Stat model of growth regulation. The coordination of growth of muscle and stature is a combination of genetic programming, and of two-way mechanical interactions involving the mechanotransduction of muscle growth through stretching by bone length growth, the core Protein-Stat feature, and the strengthening of bone through muscle contraction via the mechanostat. Thus, growth in bone length is the initiating event and this is always observed. Endocrine and cellular mechanisms of growth in stature are reviewed in terms of the growth hormone-insulin like growth factor-1 (GH-IGF-1) and thyroid axes and the sex hormones, which together mediate endochondral ossification in the growth plate and bone lengthening. Cellular mechanisms of muscle growth during development are then reviewed identifying (a) the difficulties posed by the need to maintain its ultrastructure during myofibre hypertrophy within the extracellular matrix and the concept of muscle as concentric “bags” allowing growth to be conceived as bag enlargement and filling, (b) the cellular and molecular mechanisms involved in the mechanotransduction of satellite and mesenchymal stromal cells, to enable both connective tissue remodelling and provision of new myonuclei to aid myofibre hypertrophy and (c) the implications of myofibre hypertrophy for protein turnover within the myonuclear domain. Experimental data from rodent and avian animal models illustrate likely changes in DNA domain size and protein turnover during developmental and stretch-induced muscle growth and between different muscle fibre types. Growth of muscle in male rats during adulthood suggests that “bag enlargement” is achieved mainly through the action of mesenchymal stromal cells. Current understanding of the nutritional regulation of protein deposition in muscle, deriving from experimental studies in animals and human adults, is reviewed, identifying regulation by amino acids, insulin and myofibre volume changes acting to increase both ribosomal capacity and efficiency of muscle protein synthesis via the mechanistic target of rapamycin complex 1 (mTORC1) and the phenomenon of a “bag-full” inhibitory signal has been identified in human skeletal muscle. The final section deals with the nutritional sensitivity of growth of muscle and stature to dietary protein in children. Growth in length/height as a function of dietary protein intake is described in the context of the breastfed child as the normative growth model, and the “Early Protein Hypothesis” linking high protein intakes in infancy to later adiposity. The extensive paediatric studies on serum IGF-1 and child growth are reviewed but their clinical relevance is of limited value for understanding growth regulation; a role in energy metabolism and homeostasis, acting with insulin to mediate adiposity, is probably more important. Information on the influence of dietary protein on muscle mass per se as opposed to lean body mass is limited but suggests that increased protein intake in children is unable to promote muscle growth in excess of that linked to genotypic growth in length/height. One possible exception is milk protein intake, which cohort and cross-cultural studies suggest can increase height and associated muscle growth, although such effects have yet to be demonstrated by randomised controlled trials.

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SWELL1 regulates skeletal muscle cell size, intracellular signaling, adiposity and glucose metabolism

Cited by 48 publications

References 69 publications

The SWELL1-LRRC8 complex regulates endothelial AKT-eNOS signaling and vascular function

The SWELL1-LRRC8 complex regulates endothelial AKT-eNOS signaling and vascular function

Small molecule SWELL1-LRRC8 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes

Interactions between Growth of Muscle and Stature: Mechanisms Involved and Their Nutritional Sensitivity to Dietary Protein: The Protein-Stat Revisited

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