The <scp>mTORC2</scp> Component Rictor Is Required for Load‐Induced Bone Formation in Late‐Stage Skeletal Cells

Lewis, Karl J.; Yi, Xin; Wright, Christian S; Pemberton, Emily Z.; Bullock, Whitney A.; Thompson, William R.

doi:10.1002/jbm4.10366

Cited by 10 publications

(12 citation statements)

References 37 publications

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“…β-catenin and YAP1 are mechanoresponsive proteins that modulate these processes in mesenchymal stem/stromal cells (MSCs) [1][2][3] . β-catenin nuclear localization occurs after dynamic strain 1,[4][5][6] , which concurrently induces actin rearrangement into F-actin cables which arch over the nucleus 7 and connect to the inner nuclear membrane through actin's association with the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex 8 . YAP1 nuclear translocation is also modulated by cytoskeletal actin fibers which form in response to forces generated after adherence to stiff substrates 2 , but has not been studied with respect to dynamic strain.…”

Section: Introductionmentioning

confidence: 99%

Mechanically Induced Nuclear Shuttling of β-Catenin Requires Co-transfer of Actin

et al. 2022

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Mesenchymal stem cells (MSC) respond to environmental forces with both cytoskeletal re-structuring and activation of protein chaperones of mechanical information, β-catenin and Yes-Associated Protein 1 (YAP1). To function, MSCs must differentiate between dynamic forces such as cyclic strains of extracellular matrix due to physical activity and static strains due to ECM stiffening. To delineate how MSCs recognize and respond differently to both force types, we compared effects of dynamic (200 cycles x 2%) and static (1 x 2% hold) strain on nuclear translocation of β-catenin and YAP1 at 3h after force application. Dynamic strain induced nuclear accumulation of β-catenin, and increased cytoskeletal actin structure and cell stiffness, but had no effect on nuclear YAP1 levels. Critically, both nuclear actin and nuclear stiffness increased along with dynamic strain-induced β-catenin transport. Augmentation of cytoskeletal structure using either static strain or lysophosphatidic acid (LPA) did not increase nuclear content of βcatenin or actin, but induced robust nuclear increase in YAP1. As actin binds β-catenin, we considered whether β-catenin, which lacks a nuclear localization signal, was dependent on actin to gain entry to the nucleus. Knockdown of cofilin-1 (Cfl1) or importin-9 (Ipo9), which co-mediate nuclear transfer of G-actin, prevented dynamic strain-mediated nuclear transfer of both β-catenin and actin. In sum, dynamic strain induction of actin re-structuring promotes nuclear transport of G-actin, concurrently supporting nuclear access of β-catenin via mechanisms utilized for actin transport. Thus, dynamic and static strain activate alternative mechanoresponses reflected by differences in the cellular distributions of actin, β-catenin and YAP1.

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Section: Introductionmentioning

confidence: 99%

Mechanically Induced Nuclear Shuttling of β-Catenin Requires Co-transfer of Actin

et al. 2022

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“…51,52 This increase in activity likely requires increased energy and protein production by osteoblasts. Consistent with this idea, the deletion of Rictor, an mTOR complex 2 subunit, in mature osteoblasts blunts the anabolic response to mechanical stimuli in adult mice, 53 suggesting that cell metabolism is critical for the anabolic response. In previous studies, we and others showed that deletion of Piezo1 in osteoblast lineage cells decreases the bone formation rate and blunts the skeletal response to mechanical loading.…”

Section: Discussionmentioning

confidence: 76%

Piezo1 stimulates mitochondrial function via cAMP signaling

Kordsmeier

Nookaew

et al. 2022

The FASEB Journal

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Mechanical signals stimulate mitochondrial function but the molecular mechanisms are not clear. Here, we show that the mechanically sensitive ion channel Piezo1 plays a critical role in mitochondrial adaptation to mechanical stimulation.The activation of Piezo1 induced mitochondrial calcium uptake and oxidative phosphorylation (OXPHOS). In contrast, loss of Piezo1 reduced the mitochondrial oxygen consumption rate (OCR) and adenosine triphosphate (ATP) production in calvarial cells and these changes were associated with increased expression of the phosphodiesterases Pde4a and lower cyclic AMP (cAMP) levels. In addition, Piezo1 increased cAMP production and the activation of a cAMP-responsive transcriptional reporter. Consistent with this, cAMP was sufficient to increase mitochondrial OCR and the inhibition of phosphodiesterases augmented the increase in OCR induced by Piezo1. Moreover, the inhibition of cAMP production or activity of protein kinase A, a kinase activated by cAMP, prevented the increase in OCR induced by Piezo1. These results demonstrate that cAMP signaling contributes to the increase in mitochondrial OXPHOS induced by activation of Piezo1.

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“…There are also growth factor-independent activation mechanisms ( Figure 2 ). For example, in specific cell types mTORC2 is involved in mechanically induced activation of β -catenin, such that inhibition of Rictor disrupts mechanically induced cytoskeletal reorganization ( Lewis et al, 2020 ). Moreover, mTORC2 can be activated by association with ribosomes ( Oh et al, 2010 ; Zinzalla et al, 2011 ).…”

Section: Mtor Regulators and Effectorsmentioning

confidence: 99%

Look who’s TORking: mTOR-mediated integration of cell status and external signals during limb development and endochondral bone growth

H’ng

Khaladkar

Roselló-Díez

2023

Front. Cell Dev. Biol.

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The balance of cell proliferation and size is key for the control of organ development and repair. Moreover, this balance has to be coordinated within tissues and between tissues to achieve robustness in the organ’s pattern and size. The tetrapod limb has been used to study these topics during development and repair, and several conserved pathways have emerged. Among them, mechanistic target of rapamycin (mTOR) signaling, despite being active in several cell types and developmental stages, is one of the least understood in limb development, perhaps because of its multiple potential roles and interactions with other pathways. In the body of this review, we have collated and integrated what is known about the role of mTOR signaling in three aspects of tetrapod limb development: 1) limb outgrowth; 2) chondrocyte differentiation after mesenchymal condensation and 3) endochondral ossification-driven longitudinal bone growth. We conclude that, given its ability to interact with the most common signaling pathways, its presence in multiple cell types, and its ability to influence cell proliferation, size and differentiation, the mTOR pathway is a critical integrator of external stimuli and internal status, coordinating developmental transitions as complex as those taking place during limb development. This suggests that the study of the signaling pathways and transcription factors involved in limb patterning, morphogenesis and growth could benefit from probing the interaction of these pathways with mTOR components.

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The mTORC2 Component Rictor Is Required for Load‐Induced Bone Formation in Late‐Stage Skeletal Cells

Cited by 10 publications

References 37 publications

Mechanically Induced Nuclear Shuttling of β-Catenin Requires Co-transfer of Actin

Mechanically Induced Nuclear Shuttling of β-Catenin Requires Co-transfer of Actin

Piezo1 stimulates mitochondrial function via cAMP signaling

Look who’s TORking: mTOR-mediated integration of cell status and external signals during limb development and endochondral bone growth

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