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Cited by 48Hippo pathway signaling and YAP/TAZSignaling Pathways in DiseaseMuscle Physiology and Disorders

The Hippo signal transduction network for exercise physiologists

Open access
Gabriel, Brendan M., Hamilton, D. Lee, Tremblay, Annie M., Wackerhage, Henning·2016·Journal of Applied Physiology
DOI 10.1152/japplphysiol.01076.2015PMC PMC4867322
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Abstract

The ubiquitous transcriptional coactivators Yap (gene symbol Yap1) and Taz (gene symbol Wwtr1) regulate gene expression mainly by coactivating the Tead transcription factors. Being at the center of the Hippo signaling network, Yap and Taz are regulated by the Hippo kinase cassette and additionally by a plethora of exercise-associated signals and signaling modules. These include mechanotransduction, the AKT-mTORC1 network, the SMAD transcription factors, hypoxia, glucose homeostasis, AMPK, adrenaline/epinephrine and angiotensin II through G protein-coupled receptors, and IL-6. Consequently, exercise should alter Hippo signaling in several organs to mediate at least some aspects of the organ-specific adaptations to exercise. Indeed, Tead1 overexpression in muscle fibers has been shown to promote a fast-to-slow fiber type switch, whereas Yap in muscle fibers and cardiomyocytes promotes skeletal muscle hypertrophy and cardiomyocyte adaptations, respectively. Finally, genome-wide association studies in humans have linked the Hippo pathway members LATS2, TEAD1, YAP1, VGLL2, VGLL3, and VGLL4 to body height, which is a key factor in sports.

Integrity signals

Registry

Crossref · 10.1152/japplphysiol.01076.2015

Cites

180 of 180 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

109 of 179 cited sources checked · 66 supported · 2 flagged · accuracy not yet measured

  • Premisecitation
    § Cross-talk with AMPK and glucose signalling · p. 10

    AMPK phosphorylates the Yap regulator Amotl1 on Ser293.

    “These include the phosphorylation of the Yap regulator Amotl1 on Ser293 by AMPK (26)”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [26] source

      The Results section, “AMPK directly phosphorylates AMOTL1 at Ser793,” identifies Ser793—not Ser293—as the site and reports that purified AMPK phosphorylated wild-type AMOTL1 but not the S793A mutant. The cited paper therefore gives a different residue number from the citing sentence. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation
    § Hippo and satellite cells · p. 18

    Satellite cell-depleted muscle cannot maintain initial hypertrophy after more than 8 weeks.

    “However, satellite cell-depleted muscle cannot maintain the initial hypertrophy after more than 8 weeks (38),”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [38] source

      The Results report that satellite cell-depleted muscle gained 65% in mass after 2 weeks of overload and maintained that gain through 8 weeks. The Discussion says further growth plateaued, not that the initial hypertrophy was lost. The study does not report a time point beyond 8 weeks. (LLM, conf=0.93)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation
    § Hippo signal transduction pathway and network · p. 4

    Phosphorylated Lats1 and Lats2 inhibit Yap and Taz by phosphorylating multiple serine residues.

    “Phosphorylated Lats1 and Lats2 then inhibit the transcriptional co-factors Yap and Taz by phosphorylating multiple serine residues (86, 162).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [86] source

      The introduction and Discussion (page unavailable) describe LATS phosphorylation of TAZ at Ser-89 and Ser-311 as mechanisms of inhibition. The Discussion also says YAP is regulated similarly, but the passages do not establish that both LATS1 and LATS2 phosphorylate multiple serine residues on both YAP and TAZ. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [162] source

      The section “YAP is phosphorylated in vivo on multiple sites” identifies five YAP serines at Lats consensus sites, and the paper describes Lats-mediated inhibition of YAP. The passages do not establish the same phosphorylation-and-inhibition claim for TAZ. No page numbers were provided in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
  • Premisecitation
    § Mechanotransduction · p. 7

    Loss-of-function of Bag3 causes severe myopathy symptoms in mice and humans.

    “The importance of Bag3 for skeletal muscle is further demonstrated by the finding that a loss-of-function of Bag3 causes severe myopathy symptoms in mice and humans (62, 117).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [62] source

      The paper’s opening summary reports that mice with homozygous Bag3 disruption developed fulminant myopathy, and the Discussion describes severe muscle degeneration and death before four weeks. The passages about humans concern BAG3 expression, not loss-of-function causing myopathy in humans; this source supports the mouse portion of the claim but not the human portion. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [117] source

      The Discussion reports that targeted Bag3 deletion causes severe myopathy in mice and that three patients with a BAG3 mutation had severe childhood-onset muscle weakness. It describes altered function of the human mutant protein as a prediction, however, and does not establish that the patients’ mutation causes loss of function. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
  • Premisecitation
    § Mechanotransduction · p. 6

    The stiffness of the cellular environment influences differentiation of mesenchymal stem cells into muscle and other cell types.

    “Additionally, the stiffness of the cellular environment or niche is an additional mechanical signal that influences for example the differentiation of mesenchymal stem cells into muscle and other cell types (34, 35).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [34] source

      The Discussion reports that matrix stiffness affects myotube differentiation, and the Online supplemental material section says mesenchymal stem cells show myoblast-like morphology on muscle-like stiffness. The paper does not establish that stiffness directs mesenchymal stem cells to differentiate into muscle and other cell types; its discussion of stem-cell differentiation into connective tissue presents a possible mechanical explanation, not a demonstrated effect. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [35] source
  • Classified as probably not a substantial claim. 24
  • May combine two claims. 54

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Hippo signal transduction pathway and network · p. 3

    The Hippo pathway is highly conserved evolutionarily.

    “The Hippo pathway is highly conserved evolutionarily (60).”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation
    § Mechanotransduction · p. 6

    Increased cell-cell contact reduces mechanical loading of cells, which explains deactivation of Yap and Taz at high cell density.

    “Later, it was shown that increased cell-cell contact reduces the mechanical loading of cells, which explained the previously observed (163) deactivation of Yap and Taz in response to cell-cell contact at high cell density (8).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [163] source

      The section “YAP localization and phosphorylation are regulated by cell density” reports that YAP moves from the nucleus to the cytoplasm and becomes phosphorylated at high cell density. This supports the cited observation for YAP, but our copy does not establish the same response for TAZ. It explains YAP regulation through Hippo-pathway phosphorylation, not reduced mechanical loading; the sentence appears to attribute that later explanation to a different citation. Page numbers are unavailable in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [8] source

  • May combine two claims.

    Premisecitation
    § Cross-talk with AMPK and glucose signalling · p. 11

    Hippo signalling responds to glucose and regulates the expression of glucose transporters.

    “Also, because Hippo signalling responds to glucose and regulates the expression of glucose transporters (145)”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation
    § Mechanotransduction · p. 7

    BAG3 expression decreases after acute high intensity resistance exercise, but increases together with force-bearing cytoskeleton proteins.

    “Also, BAG3 expression decreases after acute high intensity resistance exercise, but increases together with force-bearing cytoskeleton proteins (136).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [136] source

      The supplied Abstract passage reports that BAG3 protein fell to 63% of its resting level 24 hours after a single bout of maximal eccentric resistance exercise. It also reports that BAG3 and force-bearing proteins increased, but only after sustained training with progressively increasing load—not as part of the acute response. The claim omits that distinction. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation
    § Cross-talk with hypoxia signalling · p. 11

    Hif1α promotes the expression of Taz and Taz transactivates Hif1α, indicating reciprocal co-activation.

    “Hif1 α also promotes the expression of Taz and Taz transactivates Hif1 α , highlighting a mechanism by which Taz and Hif1 α are acting as reciprocal co-activators (153).”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation
    § Cross-talk with myostatin-Smad signalling · p. 9

    Several mechanisms have been proposed for how Yap or Taz interact with Smads, including binding to Smad7, promotion of Smad1 transcriptional action, and effects on Smad2/3 localisation.

    “Several mechanisms have been proposed that can explain how Yap or Taz can interact with Smads. These include the binding of Yap to the inhibitory Smad7 (7, 49), the promotion of Smad1 transcriptional action by Yap binding (3), and an effect of Yap and Taz on Smad2/3 localisation (137).”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [7] source
    • cites [49] Guo J, 2006, Int J Mol Med source
    • cites [3] source

  • May combine two claims.

    Premisecitation
    § Cross-talk with Akt-Tsc-mTOR signalling · p. 8

    Akt phosphorylates Mst1 on Thr387 and Thr120, suggesting that Akt1 and Mst1 regulate each other's activity.

    “Conversely, Akt phosphorylates Mst1 on Thr387 (65) and Thr120 (161), suggesting that Akt1 and Mst1 regulate each other's activity.”
    Quote in the paperNot a substantial claim2 of 2 sources checked

  • May combine two claims.

    Premisecitation
    § Cross-talk with myostatin-Smad signalling · p. 9

    Both Yap and Bmp4 stimulate satellite cell proliferation while inhibiting differentiation into myotubes.

    “This is intriguing because both Yap (67) and Bmp4 (109) stimulate satellite cell proliferation while inhibiting differentiation into myotubes.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [67] source
      Experimental — accuracy not yet measured
    • cites [109] source

  • May combine two claims.

    Premisecitation
    § Cross-talk with Akt-Tsc-mTOR signalling · p. 8

    Akt was initially shown to phosphorylate Yap on Ser127, but this finding was not confirmed by subsequent studies.

    “Akt was initially shown to phosphorylate Yap on Ser127 (13) but this finding was not confirmed by subsequent studies.”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation
    § Cross-talk with AMPK and glucose signalling · p. 10

    Both glucose starvation and AMPK activators inhibit Yap in different cell types.

    “Both glucose starvation (36, 100, 145) and AMPK activators (26, 100, 145) inhibit Yap in different cell types.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [36] source
      Experimental — accuracy not yet measured
    • cites [100] source
      Experimental — accuracy not yet measured
    • cites [145] source
      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation
    § Hippo and satellite cells · p. 18

    High Yap activity from expression of constitutively active YAP1 S127A promotes proliferation but inhibits differentiation.

    “Again, high Yap activity resulting from the expression of the constitutively active YAP1 S127A mutant promotes proliferation but inhibits differentiation (67).”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Interleukin-6 and Hippo · p. 13

    Interleukin-6 is a myokine produced by contracting muscle but its functions are incompletely understood.

    “Interleukin-6 is a myokine (i.e. a circulating signalling molecule) that is produced by contracting muscle but whose functions are incompletely understood (106, 110).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [106] source
    • cites [110] source

  • May combine two claims.

    Premisecitation
    § Hippo and skeletal muscle hypertrophy · p. 17

    YAP induced MyoD and Myc reporters while inhibiting a Smad binding element (CAGA)-containing reporter.

    “Additionally, they found that YAP induced MyoD and Myc reporters, whilst inhibiting a Smad binding element (CAGA)-containing reporter (46).”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation
    § Hippo and skeletal muscle hypertrophy · p. 17

    Overexpressing the predominant YAP isoform in mouse muscle via rAAV6 increased muscle mass, cross-sectional area, and protein synthesis.

    “Additionally, they used the same rAAV6 system to over express the predominant YAP isoform in muscle and found increases in muscle mass, cross sectional area and protein synthesis (Table 1, (148)).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [148] source
      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation
    § Hippo and skeletal muscle hypertrophy · p. 17

    Reducing Yap levels in mouse limb muscles via rAAV6-mediated shRNA decreased muscle fibre size and protein synthesis.

    “They found a decreased muscle fibre size and reduced protein synthesis (148).”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation
    § Hippo and skeletal muscle hypertrophy · p. 16

    mTOR signalling is a key mediator of muscle protein synthesis, as shown by rapamycin inhibiting the increase in muscle protein synthesis after resistance exercise in human muscle.

    “A key mediator of muscle protein synthesis is mTOR signalling, as shown for example by the inhibitory effect of rapamycin on the increase of muscle protein synthesis after resistance exercise in human muscles (30).”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation
    § Hippo and adaptive changes in skeletal muscle fibre phenotypes · p. 16

    CKM-driven Tead1 overexpression reduced the shortening velocity and increased the contraction and relaxation times of extensor digitalis longus muscles.

    “Functionally, CKM-driven Tead1 overexpression reduced the shortening velocity (Vmax) and increased the contraction and relaxation times of extensor digitalis longus muscles (132).”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation
    § Hippo and skeletal muscle hypertrophy · p. 17

    Fibres overexpressing YAP were larger than control fibres, demonstrating that elevated YAP activity can cause hypertrophy.

    “The fibres overexpressing YAP were larger than control fibres, demonstrating that elevated YAP activity could cause hypertrophy ( Table 1 ).”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation
    § Hippo and the Athlete's heart · p. 20

    Two recent studies found that both cardiac stem cells and cardiomyocytes proliferate in response to endurance exercise in rodents.

    “Two recent studies found that both cardiac stem cells and cardiomyocytes proliferate in response to endurance exercise in rodents (80, 146).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [80] source

      The Results section reports more c-Kit+ cardiac stem cells in swimming-trained mice than in sedentary mice. The Discussion proposes proliferation as a possible explanation but says the mechanism remains under investigation. The paper measures cardiomyocyte enlargement, not cardiomyocyte proliferation, so it does not establish that both cell types proliferated in response to exercise. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [146] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Hippo & body height · p. 22

    Dwarfism can be caused by FGFR3 mutations.

    “Examples for the latter are dwarfism caused by FGFR3 mutations (37),”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Hippo & body height · p. 22

    Body height depends on hundreds, if not thousands, of common DNA sequence variations with small effect size.

    “and depends on hundreds, if not thousands, of common DNA sequence variations with a small effect size (152).”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation
    § Hippo and the Athlete's heart · p. 19

    Electrocardiographic studies show that athletes have enlarged hearts, later confirmed by comparative echocardiography on endurance athletes.

    “Indeed, electrocardiographic studies show that athletes have enlarged hearts (9) which was later confirmed by comparative echocardiography on endurance athletes (91).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [9] Arstila M, 1966, J Sports Med Phys Fitness
    • cites [91] source

  • May combine two claims.

    Premisecitation
    § Hippo and the Athlete's heart · p. 21

    Yap is activated in hearts stressed by pathological pressure overload and in the area bordering a myocardial infarction in mice.

    “Furthermore, Yap is activated in hearts stressed by pathological pressure overload (144) and in the area bordering a myocardial infarction in mice (25).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [144] source
    • cites [25] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Hippo & body height · p. 23

    A female-specific SNP in LIN28B is associated with late pubertal growth.

    “Another interesting association of the study by Cousminer et al. is the identification of a female-specific SNP in LIN28B associated with late pubertal growth (23).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [23] source

      The Results (p. 4) identify rs7759938 near LIN28B as a variant associated with pubertal growth. The paper defines late pubertal growth separately in Phenotypes and study subjects (p. 11), but the retrieved passages do not establish that this LIN28B association is female-specific or specifically concerns late pubertal growth. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Hippo & body height · p. 23

    The LIN28/LET-7 pathway is a potent regulator of organismal development and cellular metabolism.

    “The LIN28/LET-7 pathway, which has recently emerged as a potent regulator of organismal development and cellular metabolism (120),”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation
    § Hippo and the Athlete's heart · p. 19

    Cardiac output is one of the key predictors of VO2max and determines the efficiency of oxygen transport to exercising musculature.

    “Early physiological studies in humans demonstrated that one of the key predictors of an individual's VO 2 max is the blood flow generated by the heart, termed cardiac output (99), which determines the efficiency of oxygen transport to the exercising musculature.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [99] source

      The Discussion identifies cardiac output as a main circulatory determinant of maximal oxygen intake. But the Conclusions state that maximal oxygen intake depends on both cardiac output and the arteriovenous oxygen difference; the paper does not establish that cardiac output alone determines the efficiency of oxygen transport to exercising muscle. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation
    § Hippo and the Athlete's heart · p. 21

    Yap1 overexpression in cultured neonatal rat cardiomyocytes promotes hypertrophy and survival compared to control cardiomyocytes.

    “First, Yap1 overexpression in cultured neonatal rat cardiomyocytes promotes hypertrophy and survival compared to control cardiomyocytes (25).”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation
    § Hippo and the Athlete's heart · p. 20

    There is emerging evidence for a cardiac stem cell population that may engage in limited regeneration in addition to low-rate renewal of preexisting cardiomyocytes.

    “There is emerging evidence supporting the existence of a cardiac stem cell population that may engage in some limited regeneration processes (32) in addition to a low rate renewal of preexisting cardiomyocytes (119).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [32] source
    • cites [119] source

  • May combine two claims.

    Premisecitation
    § Hippo and the Athlete's heart · p. 22

    In a mouse model of myocardial infarction, forcing human YAP expression in the heart via adeno-associated virus delivery increases cardiomyocyte proliferation and improves cardiac function and survival.

    “Finally, in a mouse model of myocardial infarction, forcing human YAP expression in the heart using adeno-associated virus delivery increases cardiomyocyte proliferation and improves cardiac function as well as survival (85).”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Hippo & body height · p. 23

    The LIN28/LET-7 pathway has been functionally linked with the Hippo pathway.

    “has been functionally linked with the Hippo pathway (21, 104).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [21] source
    • cites [104] source

      The Introduction identifies LIN28A/B as inhibitors of Microprocessor and describes Hippo signaling as a regulator of Microprocessor activity. The Results demonstrate Hippo-dependent processing of other miRNAs, but the passages found do not establish a functional link between the LIN28/LET-7 pathway and Hippo signaling (searched: LIN28, let-7, Hippo and YAP). (LLM, conf=0.73)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Hippo & body height · p. 22

    Body height is approximately 70-90% inherited.

    “Body height is approximately 70-90% inherited (121)”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Interpretationcitation
    § Hippo & body height · p. 23

    Common DNA sequence variants in several Hippo genes influence body height, but the effect of each variant on height is small.

    “In summary, common DNA sequence variants in several Hippo genes influence body height but the effect of each variant on height is small, presumably as de novo DNA sequence variants with a large effect size either become fixed or lost relatively quickly (17).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [17] source

      The section “Common variants: lessons from a decade of genome-wide association studies” reports that many common SNPs are associated with adult height and describes common variants as typically having small effect sizes (page unavailable). It does not identify those variants as being in Hippo genes, so the gene-specific part of the claim is unsupported. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation
    § Endurance exercise-associated signals linked to YAP/TAZ · p. 47

    Glucose and AMPK are endurance-exercise-related signals that have been linked to YAP/TAZ.

    “Endurance exercise-associated signals linked to YAP/TAZ”
    • Also stated in: § Glucose, AMPK · p. 47 · plain
      “Glucose, AMPK”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites DeRan et al Cell Rep (2014) source

      The Results section (page not provided) links glucose deprivation and AMPK activation to YAP regulation and reports increased YAP and TAZ phosphorylation after treatment with an AMPK activator. It does not examine endurance exercise or establish that these are endurance-exercise-associated signals. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites Mo et al Nature Cell Biol (2015) source
    • cites Wang et al Nature Cell Biol (2015) source

      The Results sections on glucose homeostasis and AMPK show that glucose availability affects YAP phosphorylation and that AMPK associates with and phosphorylates YAP (pages not provided). The paper therefore supports a link between both signals and YAP, but our copy does not establish that they are endurance-exercise-associated signals or show a corresponding link to TAZ. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation
    § Endurance exercise-associated signals linked to YAP/TAZ · p. 47

    Adrenaline (epinephrine), angiotensin 2, and G protein-coupled receptors are endurance-exercise-related signals linked to YAP/TAZ.

    “Endurance exercise-associated signals linked to YAP/TAZ”
    • Also stated in: § Adrenaline (epinephrine), angiotensin 2, G protein-coupled receptors · p. 47 · plain
      “Adrenaline (epinephrine), angiotensin 2, G protein-coupled receptors”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Yu et al Cell (2012) source

      The Results section (“Regulation of YAP phosphorylation by GPCRs”; page unavailable) links epinephrine and GPCR signaling to YAP/TAZ phosphorylation. It also reports an effect from overexpressing an angiotensin II receptor, but does not show an effect of angiotensin II itself. These passages do not establish that the signals are associated with endurance exercise. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S4 (based).

    Findingnone given
    § Introduction · p. 3

    Only few studies on Hippo in an exercise context have been published.

    “However, to date only few studies on Hippo in an exercise context have been published.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given
    § Hippo signal transduction pathway and network · p. 3

    In mammals, two homologues of the fly hippo gene exist, namely Mst1 and Mst2.

    “In mammals (see Figure 1 for a schematic of the mammalian Hippo pathway), two homologues of the fly hippo gene exist, namely the upstream kinases Mst1 ( Stk4 ) and Mst2 ( Stk3 ).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given
    § Hippo signal transduction pathway and network · p. 3

    Mst1 and Mst2 activate Lats1 and Lats2 with the help of scaffolding proteins.

    “With the help of scaffolding proteins, Mst1 and Mst2 activate the downstream kinases Lats1 and Lats2.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Mechanotransduction · p. 7

    Bag3 mediates tension-induced autophagy, which might contribute to increased protein breakdown during resistance exercise.

    “One Hippo-independent function of Bag3 is to mediate tension-induced autophagy, which might contribute to the increased protein breakdown observed during resistance exercise (127).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [127] source

  • May combine two claims.

    Premisereasoning
    § Abstract 35 · p. 2

    Yap and Taz are at the centre of the Hippo signalling network and are regulated by the Hippo kinase cassette and by many exercise-associated signals and signalling modules.

    “Being at the centre of the Hippo signalling network, Yap and Taz are regulated by the Hippo 38 kinase cassette and additionally by a plethora of often exercise-associated signals and 39 signalling modules.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Mechanotransduction · p. 7

    Bag3 contains a WW domain.

    “Importantly, Bag3 contains a WW domain, a rare protein domain frequently found in Hippo members (WW indicates two tryptophan residues; reviewed by (124)).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [124] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given
    § Abstract 35 · p. 2

    Genome-wide association studies in humans have linked Hippo pathway members LATS2, TEAD1, YAP1, VGLL2, VGLL3 and VGLL4 to body height.

    “Finally, genome wide-association studies in humans have linked 47 the Hippo pathway members LATS2, TEAD1, YAP1, VGLL2, VGLL3 and VGLL4 to body 48 height”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given
    § Sensing of catecholamines and other G protein-coupled receptors (GPCRs) ligands 273 · p. 12

    Catecholamine concentrations generally increase with the intensity and duration of exercise and drive systemic responses via α- and β-adrenergic receptors.

    “Catecholamine concentrations generally increase with the intensity and duration of exercise and drive the systemic responses to exercise via the α - and β -adrenergic receptors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Cross-talk with AMPK and glucose signalling · p. 10

    Exercise increases the concentrations of AMP and ADP in contracting skeletal and cardiac muscle and depletes glycogen, especially in muscle.

    “Indeed, exercise increases the concentrations of AMP and ADP in contracting skeletal and cardiac muscle and exercise depletes glycogen, especially in muscle (45).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [45] source

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning
    § Cross-talk with AMPK and glucose signalling · p. 11

    Energy stress and AMPK regulate Yap, suggesting that Yap should be affected by exercise and diet.

    “The fact that energy stress and the key exercise kinase AMPK regulate Yap suggest that Yap should be affected by exercise and diet.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Cross-talk with myostatin-Smad signalling · p. 9

    Smad2/3-4 complexes promote muscle loss, whereas Smad1/3/5-4 complexes have been proposed to promote muscle growth.

    “Smads compete for the common mediator Smad4 to form either transcriptionally active Smad2/3-4 complexes promoting muscle loss or Smad1/3/5-4 complexes that have recently been proposed to promote muscle growth (114).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [114] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Cross-talk with AMPK and glucose signalling · p. 10

    During the transition from rest to exercise, ATP turnover can rise potentially more than 200 fold.

    “During the transition from rest to exercise ATP turnover can rise potentially more than 200 fold (98).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [98] Meyer RA, 1996 source

  • May combine two claims.

    Premisecitation
    § Cross-talk with hypoxia signalling · p. 11

    Yap directly interacts with and stabilises Hif1α.

    “Additionally, Yap directly interacts with and stabilises Hif1 α (88).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [88] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Cross-talk with hypoxia signalling · p. 11

    Altitude training is often used to stimulate the molecular adaptations to hypoxia, including EPO-mediated haematopoiesis that increases oxygen transport capacity.

    “Moreover, altitude training is often used to stimulate the molecular adaptations to hypoxia, including the EPO-mediated haematopoiesis that increases the athlete's oxygen transport capacity (118).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [118] source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given
    § Cross-talk with myostatin-Smad signalling · p. 8

    TGFβ and BMPs bind to activin receptors.

    “TGFβ and BMPs are two classes of small extracellular molecules that bind to activin receptors.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given
    § Cross-talk with myostatin-Smad signalling · p. 8

    Bound activin receptors phosphorylate either Smad2/3 or Smad1/5/8 proteins.

    “Bound activin receptors then either phosphorylate the receptor-regulated Smad2/3 or Smad1/5/8 proteins, respectively.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Cross-talk with hypoxia signalling · p. 11

    Hypoxia activates the E3 ligase Siah2, which leads to degradation of Lats2, resulting in decreased Yap phosphorylation and increased Yap activity in the nucleus.

    “For example, hypoxia activates the E3 ligase Siah2, which leads to the degradation of Lats2. This results in a decreased level of Yap phosphorylation, increasing the activity of Yap in the nucleus (88).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [88] source

  • May combine two claims.

    Interpretationreasoning
    § Hippo and satellite cells · p. 19

    Yap promotes myoblast and satellite cell proliferation but inhibits differentiation into myotubes and muscle fibres.

    “Collectively, these results indicate that Yap promotes myoblast and satellite cell proliferation but inhibits differentiation into myotubes and muscle fibres.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Hippo and skeletal muscle hypertrophy · p. 16

    Mechanosensing and Hippo signalling are extensively linked, including via the Z-disc-localized Bag3 mechanosensor in skeletal muscle.

    “including the Z-disc located Bag3 mechanosensor in skeletal muscle (135, 136).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [50] source
    • cites [87] source
    • cites [135] source

  • May combine two claims.

    Premisecitation
    § Hippo and skeletal muscle hypertrophy · p. 16

    After resistance exercise, both muscle protein synthesis and breakdown increase.

    “After resistance exercise, protein synthesis and protein breakdown both increase.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [128] source

  • May combine two claims.

    Premisecitation
    § Sensing of catecholamines and other G protein-coupled receptors (GPCRs) ligands 273 · p. 12

    Angiotensin II contributes to the adaptation to overload-induced skeletal muscle hypertrophy and stretch-induced cardiac hypertrophy.

    “Also, angiogensin II contributes to the adaptation to overload-induced skeletal muscle hypertrophy (47) and stretch-induced cardiac hypertrophy (112).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [47] source
    • cites [112] source

  • May combine two claims.

    Premisecitation
    § Hippo and satellite cells · p. 18

    Yap is active in proliferating C2C12 myoblasts, and high Yap activity promotes their proliferation but inhibits myogenic differentiation.

    “Yap is active in proliferating C2C12 myoblasts, and high Yap activity promotes their proliferation but inhibits myogenic differentiation (147).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [147] source

  • May combine two claims.

    Interpretationcitation
    § Hippo and adaptive changes in skeletal muscle fibre phenotypes · p. 16

    Hippo signalling affects muscle fibre type-specific gene expression and fibre type percentages.

    “This suggests that Hippo signalling affects muscle fibre type-specific gene expression and fibre type percentages.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Hippo and skeletal muscle hypertrophy · p. 16

    In the fed state, muscle protein synthesis exceeds breakdown, causing protein accretion and hypertrophy.

    “In the fed state, protein synthesis is higher than breakdown, resulting in protein accretion and hypertrophy (128).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [128] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Hippo and adaptive changes in skeletal muscle fibre phenotypes · p. 15

    They observed a non-significant increase from 32% to 36% in the frequency of slow type 1 fibres in response to endurance training.

    “They also observed a non-significant increase from 32% to 36% in the frequency of slow type 1 fibres in response to endurance training (43).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] source

  • May combine two claims.

    Premisecitation
    § Hippo and skeletal muscle hypertrophy · p. 16

    In the first study on Hippo signalling and exercise, chronic stretch overload induced hypertrophy of the anterior latissimus dorsi muscle and increased skeletal α-actin gene expression.

    “In the first study on Hippo signalling in relation to exercise, the Booth group used chronic stretch overload to induce hypertrophy of the anterior latissimus dorsi muscle and found an increased expression of the skeletal α-actin gene.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given
    § Hippo & exercise-related phenomena · p. 13

    Body height is associated with single nucleotide polymorphisms in the vicinity of Hippo genes.

    “Additionally, we review emerging evidence that body height is associated with single nucleotide polymorphisms (SNPs) in the vicinity of Hippo genes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Hippo and the Athlete's heart · p. 19

    Twenty days of bed rest reduces resting heart volume by approximately 10% and exercise cardiac output by 15%, resulting in significantly reduced VO2max.

    “They showed that 20 days of bed rest reduces resting heart volume by approximately 10% and exercise cardiac output by 15%, resulting in a significantly reduced VO 2 max (113).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] Saltin B, 1968, Circulation source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Hippo & body height · p. 22

    In rare cases, body height can be affected by single, rare mutations with large effect size.

    “In rare cases, body height can be affected by single, rare mutations with a large effect size.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § Hippo and the Athlete's heart · p. 20

    The development of the athlete's heart increases VO2max and aerobic exercise capacity.

    “Consequently, this results in the development of the athlete's heart, which in turn increases the VO 2 max and aerobic exercise capacity of an individual.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Hippo and the Athlete's heart · p. 20

    Pathological hypertrophy often decompensates, reducing cardiac function and resulting in end-stage heart failure.

    “In contrast, pathological hypertrophy often decompensates, reducing cardiac function and resulting in end-stage heart failure (72).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [72] source

  • May combine two claims.

    Interpretationcitation
    § Hippo and the Athlete's heart · p. 22

    Available studies suggest that Yap can promote cardiomyocyte hypertrophy in some contexts, while in other contexts Yap appears to promote cardiomyocyte proliferation and enhance cardiac regeneration after injury.

    “Available studies suggest that Yap can promote cardiomyocyte hypertrophy in some contexts, while, in other contexts, Yap appears to promote cardiomyocyte proliferation and enhance cardiac regeneration after injury.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § Hippo and the Athlete's heart · p. 20

    Endurance exercise increases left ventricular volume, thickness, and pumping performance.

    “Collectively, these data demonstrate that endurance exercise increases left ventricular volume, thickness and pumping performance”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Hippo and the Athlete's heart · p. 21

    Yap is expressed at higher levels and dephosphorylated (activated) in samples from pathologically hypertrophied human hearts.

    “Yap is expressed at higher levels and dephosphorylated (activated) in samples obtained from pathologically hypertrophied human hearts (144).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [144] source

  • May combine two claims.

    Premisecitation
    § Hippo and the Athlete's heart · p. 19

    VO2max and cardiac output respond to exercise training and detraining.

    “The VO2max and cardiac output parameters respond to exercise training and detraining, as demonstrated by Saltin and colleagues (113).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] Saltin B, 1968, Circulation source

  • May combine two claims.

    Premisecitation
    § Hippo and the Athlete's heart · p. 22

    Yap1 S112A overexpression in cardiomyocytes improves cardiac regeneration after myocardial infarction in neonatal and adult mice, with increased cardiomyocyte proliferation compared to controls.

    “Similarly, Yap1 S112A overexpression in cardiomyocytes improves cardiac regeneration after myocardial infarction, both in neonatal and adult mice, with evidence for increased cardiomyocyte proliferation compared to controls (154).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [154] source

  • May combine two claims.

    Premisecitation
    § Hippo and the Athlete's heart · p. 22

    Knocking out Sav1 or Lats1/2 in adult mouse cardiomyocytes increases proliferation, promotes regeneration after myocardial infarction, and reduces scar tissue formation.

    “Knocking out the Hippo members Sav1 or Lats1/2 in adult mouse cardiomyocytes increases proliferation, promotes regeneration after myocardial infarction and reduces scar tissue formation (58).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [58] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Hippo & body height · p. 22

    Acromegaly can result from AIP gene mutations.

    “and acromegaly resulting from AIP gene mutations (20).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Hippo and the Athlete's heart · p. 19

    VO2max is associated with longevity.

    “and is also associated with longevity (15).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] source

  • May combine two claims.

    Premisecitation
    § Hippo and the Athlete's heart · p. 20

    Physiological hypertrophy associated with exercise or pregnancy differs from pathological hypertrophy in stimuli, structural response, absence of fibrosis, and molecular drivers.

    “Physiological hypertrophy, which is associated with exercise or pregnancy, differs from pathological hypertrophy by the nature of the stimuli, the structural response, the absence of fibrosis and the molecular drivers leading to the adaptation (94).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [94] source
74 of 74

  • The paper relies on this without support.

    Physiological hypertrophy does not progress into cardiac dysfunction.

    “Generally, physiological hypertrophy does not progress into cardiac dysfunction.”
1 of 1

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Wwtr1 is identified as both Salvador and Taz

    Minor

    The table labels Wwtr1 as Salvador, while the abstract identifies Wwtr1 as the gene for Taz. The experiment's target is therefore inconsistent within the paper.

  • BMP-related Smad complex does not match the listed Smad class

    Minor

    The text identifies Smad1/5/8 as one receptor-regulated class, then describes that class forming a Smad1/3/5-4 complex. The latter substitutes Smad3 for Smad8, although Smad3 was assigned to the other class.

2 of 2

Cited works that were retracted

Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.

  • Cites a retracted work: 10.1074/jbc.m109.059675

    Info

    The cited work was retracted on 2016-10-21 (notice 10.1074/jbc.a109.059675), not before this paper was published (2016-05-15).

    Cited work 10.1074/jbc.m109.059675 · retracted 2016-10-21 · notice 10.1074/jbc.a109.059675 · this paper published 2016-05-15

1 of 1

Cites

1 retracted

Flagged first, then by citations

Research works printed but not linked: 4

  1. Arstila M, 1966, J Sports Med Phys Fitness, 6, 166
  2. Goldberg AL, 1975, Med Sci Sports, 7, 185
  3. Guo J, 2006, Int J Mol Med, 17, 761
  4. Sudol M, 1994, Oncogene, 9, 2145

Cited by

Sorted by citations

Related

Authors
Gabriel, B. M., Hamilton, D. L., Tremblay, A. M., & Wackerhage, H.
Affiliations
  • University of Copenhagen (DK)
  • University of Stirling (GB)
  • Boston Children's Hospital (US)
  • University of Aberdeen (GB)
Corresponding author
Wackerhage, Henning
ORCID
Venue
Journal of Applied Physiology
Publisher
American Physiological Society
Published
2016-05-15
Volume
120
Issue
10
Pages
1105-1117
ISSN
  • 0161-7567 (ISSN-L)
  • 8750-7587
  • 1522-1601
DOI
10.1152/japplphysiol.01076.2015
PMC
PMC4867322
OpenAlex
W2289655239
Cited by
48
References
172
Citations by year
2026: 2 · 2025: 6 · 2024: 5 · 2023: 3 · 2022: 10 · 2021: 3 · 2020: 7 · 2019: 3 · 2018: 5 · 2017: 2 · 2016: 1
FWCI
0.40
Type
journal article
Language
en
Open access
Locations
  • Journal of Applied Physiology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Stirling Online Research Repository (University of Stirling) (submittedVersion)
  • Own your potential (DEAKIN) (submittedVersion)
Funders
Canadian Institutes of Health Research
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
Keywords
Hippo signaling pathway, YAP, TAZ, TEAD transcription factors, exercise adaptation, mechanotransduction, Akt/mTORC1 signaling, Smad signaling, hypoxia, glucose homeostasis, AMPK, angiotensin II, G protein-coupled receptors, interleukin-6, skeletal muscle hypertrophy, body height, LATS2, VGLL3, VGLL4
MeSH terms
Animals, Humans, Physical Conditioning, Animal, Transcription Factors, Signal Transduction, Exercise, Protein Serine-Threonine Kinases, Muscle, Skeletal

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-01.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-01.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

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