Contrasting effects of Ksr2, an obesity gene, on trabecular bone volume and bone marrow adiposity

Gomez, Gustavo A.; Rundle, Charles H.; Xing, Weirong; Kesavan, Chandrasekhar; Pourteymoor, Sheila; Lewis, Robert E.; Powell, David R.; Mohan, Subburaman

doi:10.7554/elife.82810

Cited by 4 publications

(3 citation statements)

References 87 publications

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“…KSR1 is the dominant protein expressed rather than KSR2 which is one of the reasons this genetic mouse model is useful for studying the role of the MAPK pathway in hearing loss. Both proteins can act as scaffolding proteins in the MAPK pathway, but they can have different physiological functions ( Gomez et al, 2022 ; Paniagua et al, 2022 ). KSR1 was hypothesized to play more of a role in hearing loss than the KSR2 protein due to KSR1 having much higher expression in the inner ear and being required for optimal MAPK signaling.…”

Section: Discussionmentioning

confidence: 99%

KSR1 knockout mouse model demonstrates MAPK pathway's key role in cisplatin- and noise-induced hearing loss

Ingersoll,

Lutze,

Kelmann

et al. 2024

J. Neurosci.

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Hearing loss is a major disability in everyday life and therapeutic interventions to protect hearing would benefit a large portion of the world population. Here we found that mice devoid of the protein kinase suppressor of RAS 1 (KSR1) in their tissues (germline KO mice) exhibit resistance to both cisplatin- and noise-induced permanent hearing loss compared to their wild-type KSR1 littermates. KSR1 is a scaffold protein that brings in proximity the mitogen-activated protein kinase (MAPK) proteins BRAF, MEK1/2 and ERK1/2 and assists in their activation through a phosphorylation cascade induced by both cisplatin and noise insults in the cochlear cells. KSR1, BRAF, MEK1/2, and ERK1/2 are all ubiquitously expressed in the cochlea. Deleting the KSR1 protein tempered down the MAPK phosphorylation cascade in the cochlear cells following both cisplatin and noise insults and conferred hearing protection of up to 30 dB SPL in three tested frequencies in male and female mice. Treatment with dabrafenib, an FDA-approved oral BRAF inhibitor, protected male and female KSR1 wild-type mice from both cisplatin- and noise-induced hearing loss. Dabrafenib treatment did not enhance the protection of KO KSR1 mice, providing evidence dabrafenib works primarily through the MAPK pathway. Thus, either elimination of the KSR1 gene expression or drug inhibition of the MAPK cellular pathway in mice resulted in profound protection from both cisplatin- and noise-induce hearing loss. Inhibition of the MAPK pathway, a cellular pathway that responds to damage in the cochlear cells, can prove a valuable strategy to protect and treat hearing loss.Significance StatementTen percent of the world population suffers from hearing loss but this impairment may be preventable. We show that mice devoid of the KSR1 protein (KO) exhibit resistance to cisplatin- and noise-induced permanent hearing loss compared to wild-type littermates that harbor the protein. Removing KSR1 tempers down the MAPK phosphorylation cascade of BRAF-MEK-ERK induced in the cochlea following cisplatin and noise insults. Treatment of KSR1 wild-type mice following cisplatin or noise with an FDA-approved BRAF inhibitor, dabrafenib, protected the hearing and, importantly, did not confer additional protection to the KO KSR1 mice. Hence, the MAPK pathway has a unique role in responding to cochlear damage and removing KSR1 gene expression or drug inhibition of the pathway results in hearing protection.

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Section: Discussionmentioning

confidence: 99%

KSR1 knockout mouse model demonstrates MAPK pathway's key role in cisplatin- and noise-induced hearing loss

Ingersoll,

Lutze,

Kelmann

et al. 2024

J. Neurosci.

View full text Add to dashboard Cite

show abstract

“…KSR1 is the dominate isoform expressed rather than KSR2 which is one of the reasons this genetic mouse model is useful for studying the role of the MAPK pathway in hearing loss. Both isoforms can act as scaffolding proteins in the MAPK pathway, but they can have different physiological functions 28,29 . KSR1 was hypothesized to play more of a role in hearing loss than the KSR2 isoform due to KSR1 having much higher expression in the inner ear and being required for optimal MAPK signaling.…”

Section: Discussionmentioning

confidence: 99%

KSR1 knockout mouse model demonstrates MAPK pathway’s key role in cisplatin- and noise-induced hearing loss

Ingersoll,

Lutze,

Kelmann

et al. 2023

Preprint

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Hearing loss is a major disability in everyday life and therapeutic interventions to protect hearing would benefit a large portion of the world population. Here we found that mice devoid of the protein kinase suppressor of RAS 1 (KSR1) in their tissues (germline KO mice) exhibit resistance to both cisplatin- and noise- induced permanent hearing loss compared to their wild-type KSR1 littermates. KSR1 is expressed in the cochlea and is a scaffold protein that brings in proximity the mitogen-activated protein kinase (MAPK) proteins BRAF, MEK and ERK and assists in their activation through a phosphorylation cascade induced by both cisplatin and noise insults in the cochlear cells. Deleting the KSR1 protein tempered down the MAPK phosphorylation cascade in the cochlear cells following both cisplatin and noise insults and conferred hearing protection of up to 30 dB SPL in three tested frequencies in mice. Treatment with dabrafenib, an FDA- approved oral BRAF inhibitor, downregulated the MAPK kinase cascade and protected the KSR1 wild-type mice from both cisplatin- and noise-induced hearing loss. Dabrafenib treatment did not enhance the protection of KO KSR1 mice, as excepted, providing evidence dabrafenib works primarily through the MAPK pathway. Thus, either elimination of the KSR1 gene expression or drug inhibition of the MAPK cellular pathway in mice resulted in profound protection from both cisplatin- and noise-induce hearing loss. Inhibition of the MAPK pathway, a cellular pathway that responds to damage in the cochlear cells, can prove a valuable strategy to protect and treat hearing loss.Significance StatementTen percent of the world population suffers from hearing loss but this impairment may be preventable. We show that mice devoid of the KSR1 protein (KO) exhibit resistance to cisplatin- and noise-induced permanent hearing loss compared to wild-type littermates that harbor the protein. Removing KSR1 tempers down the MAPK phosphorylation cascade of BRAF-MEK-ERK induced in the cochlea following cisplatin and noise insults. Treatment of KSR1 wild-type mice following cisplatin or noise with an FDA-approved BRAF inhibitor, dabrafenib, protected the hearing and, importantly, did not confer additional protection to the KO KSR1 mice. Hence, the MAPK pathway has a unique role in responding to cochlear damage, and removing KSR1 gene expression or drug inhibition of the pathway results in hearing protection.

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“…Therefore, we speculated that folic acid intake may affect total BMD, thereby affecting bone health. The previous study found that body fat is closely related to bone health, 27,28 but it is still unclear whether the effect of folic acid on BMD is directly caused or mediated by body fat. Therefore, we analyzed the body fat rate as an intermediary factor of folic acid on BMD, and the mediating effect accounted for 82.7% of the total effect (Fig.…”

Section: The Association Between Folic Acid Intake and Total Bmd May ...mentioning

confidence: 99%

Folic acid supplementation prevents high body fat-induced bone loss through TGR5 signaling pathways

Zhang,

Wei,

Feng

et al. 2024

Food Funct.

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Contrasting effects of Ksr2, an obesity gene, on trabecular bone volume and bone marrow adiposity

Cited by 4 publications

References 87 publications

KSR1 knockout mouse model demonstrates MAPK pathway's key role in cisplatin- and noise-induced hearing loss

KSR1 knockout mouse model demonstrates MAPK pathway's key role in cisplatin- and noise-induced hearing loss

KSR1 knockout mouse model demonstrates MAPK pathway’s key role in cisplatin- and noise-induced hearing loss

Folic acid supplementation prevents high body fat-induced bone loss through TGR5 signaling pathways

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