Mechanosensing in Metabolism

Abstract

Electrical mechanosensing is a process mediated by specialized ion channels, gated directly or indirectly by mechanical forces, which allows cells to detect and subsequently respond to mechanical stimuli. The activation of mechanosensitive (MS) ion channels, intrinsically gated by mechanical forces, or mechanoresponsive (MR) ion channels, indirectly gated by mechanical forces, results in electrical signaling across lipid bilayers, such as the plasma membrane. While the functions of mechanically gated channels within a sensory context (e.g., proprioception and touch) are well described, there is emerging data demonstrating functions beyond touch and proprioception, including mechanoregulation of intracellular signaling and cellular/systemic metabolism. Both MR and MS ion channel signaling have been shown to contribute to the regulation of metabolic dysfunction, including obesity, insulin resistance, impaired insulin secretion, and inflammation. This review summarizes our current understanding of the contributions of several MS/MR ion channels in cell types implicated in metabolic dysfunction, namely, adipocytes, pancreatic β-cells, hepatocytes, and skeletal muscle cells, and discusses MS/MR ion channels as possible therapeutic targets. © 2024 American Physiological Society. Compr Physiol 14:5269-5290, 2024.

Figure 1

Mechanisms of mechanosensitive ion channel opening. Top: The force-from-lipid model involves mechanical forces directly affecting membrane tension, which results in ion channel conformational changes and opening. Middle: The force-from-tether model involves an ion channel being directly tethered to the extracellular matrix (ECM) and/or cytoskeleton which when affected by mechanical forces induces the opening of the tethered ion channel. Bottom: Indirect activation involves the transduction of mechanical forces by primary mechanosensors and subsequent activation of intracellular signaling cascades that are able to open the channel indirectly, for example, via a secondary messenger. Created with BioRender.com.

Figure 2

The roles of Piezo1, VRAC/LRRC8A (SWELL1), and TRPV4 in adipocytes. Left: Piezo1 acts to prevent adipocyte inflammation and associated insulin resistance through the negative regulation of TLR4-mediated cytokine and chemokine expression. Middle: LRRC8A, an essential subunit of VRACs, sequesters GRB2 via an LRRD-mediated interaction to prevent its inhibition of PI3K-AKT2 signaling. Right: TRPV4 promotes inflammation and insulin resistance via ERK1/2-mediated cytokine and chemokine expression. Additionally, TRPV4 reduces UCP1 expression and mitochondrial respiration through its inhibition of PGC-1α. Abbreviations: AKT2, AKT serine/threonine kinase 2; AS160, AKT substrate of 160 kDa; Cav-1, caveolin-1; ERK1/2, extracellular signal-regulated kinase 1/2; GLUT4, glucose transporter type 4; GRB2, growth factor receptor-bound protein 2; GSK-3β, glycogen synthase kinase-3 beta; IR, insulin receptor; IRS1, insulin receptor substrate 1; LRRD, leucine-rich repeat domain; PGC-1α, PPAR-γ coactivator-1α; PI3K, phosphoinositide 3-kinase; TLR4, Toll-like receptor 4; UCP1, uncoupling protein 1; VRAC, volume-regulated anion channel. Created with BioRender.com.

Figure 3

The roles of Piezo1, TRPV2, TTN3, and VRAC/LRRC8A (SWELL1) in pancreatic β-cells. Piezo1 contributes to β-cell membrane depolarization-induced opening of voltage-gated calcium channels and subsequent insulin secretion via influx of sodium, with VRAC/LRRC8A also mediating these effects via chloride efflux. Additionally, release of cytosolic GABA through VRAC acts in both an autocrine and paracrine manner to synchronize insulin secretion. TTN3 transduces mechanical forces induced by glucose uptake in pancreatic β-cells, resulting in cation influx and subsequent insulin secretion due to membrane depolarization and VGCC opening. In murine cells, swelling-induced activation of TRPV2 results in calcium influx and membrane depolarization. Activation of these channels may be a consequence of β-cell mechanical swelling due to increased osmotic load as a consequence of glucose metabolism. Abbreviations: ADP, adenosine diphosphate; ATP, adenosine triphosphate; GABA, γ-aminobutyric acid; GLUT, glucose transporter; K_ATP, ATP-sensitive K⁺ channel; TRPV2, transient receptor potential vanilloid 2; TTN3, Tentonin 3/TMEM150C; VGCC, voltage-gated calcium channel; VRAC, volume-regulated anion channel. Created with BioRender.com.

Figure 4

Mechanosensitive/mechanoresponsive channel proteins including Piezo1, VRAC/LRCC8A (SWELL1), and the TRP family of channel proteins including TRPC1, TRPC4, TRPC6, and TRPV4 embedded in the plasma membrane of skeletal muscle cells. Application of stress/load on all three classes of proteins leads to activation of the PI3K-AKT2-mTOR signaling pathway, resulting in changes in cellular metabolism, differentiation, regeneration, and hypertrophy. Created with BioRender.com.

Figure 5

Abundance of VRAC subunits LRRC8A, LRRC8B, LRRC8C, LRRC8D, and LRRC8E; PIEZO1; TMEM150C (Tentonin 3/TTN3); TRPC1; TRPC6; and TRPV4 in several murine and human tissues as determined by mass spectrometry/iBAQ and obtained from ProteomicsDB (proteomicsdb.org) (146) on July 31, 2023.