Sestrin prevents skeletal muscle atrophy
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE136866 | GEO | 2019/09/05
REPOSITORIES: GEO
Similar Datasets
Project description:Sestrin prevents skeletal muscle atrophy
| PRJNA563889 | ENA
Project description:Skeletal muscle atrophy is a consequence of many diseases, environmental insults, inactivity, age and injury. Atrophy is characterized by active degradation and removal of contractile proteins and a reduction in fiber size. Animal models have been extensively used to identify pathways leading to atrophic conditions. Here we have used genome-wide expression profiling analysis and quantitative PCR to identify the molecular changes that occur in two clinically relevant animal mouse models of muscle atrophy, hindlimb casting and Achilles tendon laceration (tenotomy). Gastrocnemius muscle samples were collected 2, 7 and 14 days after insult. The total amount of muscle loss as measured by wet weight and muscle fiber size was equivalent between models, although tenotomy resulted in a more rapid induction of muscle atrophy. Furthermore, tentomy resulted in the regulation of significantly more mRNA transcripts then casting. Analysis of the regulated genes and pathways suggest that the mechanism of atrophy is distinct between these models. The degradation following casting appears ubiquitin-proteasome-mediated while degradation following tenotomy appears lysosomal and matrix-metalloproteinase (MMP)-mediated. This data suggests that there are multiple mechanisms leading to muscle atrophy and that specific therapeutic agents may be necessary to combat the atrophy seen under different conditions.
2011-10-25 | GSE25908 | GEO
Project description:Cancer cachexia is a prevalent and often fatal wasting condition that cannot be fully reversed with nutritional interventions. Muscle atrophy is a central component of the syndrome, but the mechanisms whereby cancer leads to skeletal muscle atrophy are not well understood. We performed single nucleus multi-omics on skeletal muscles from a mouse model of cancer cachexia and profiled the molecular changes in cachexic muscle. Our results revealed the activation of a denervation-induced gene program that upregulates the transcription factor myogenin. Further studies showed that a myogenin-myostatin pathway promotes muscle atrophy in response to cancer cachexia. shRNA inhibition of myogenin or inhibition of myostatin through overexpression of its endogenous inhibitor follistatin prevented cancer cachexia-induced muscle atrophy in mice. Our findings uncover a molecular basis of cancer cachexia-induced muscle atrophy and highlight potential therapeutic targets for this disorder.
2024-07-12 | GSE272085 | GEO
Project description:Cancer cachexia is a prevalent and often fatal wasting condition that cannot be fully reversed with nutritional interventions. Muscle atrophy is a central component of the syndrome, but the mechanisms whereby cancer leads to skeletal muscle atrophy are not well understood. We performed single nucleus multi-omics on skeletal muscles from a mouse model of cancer cachexia and profiled the molecular changes in cachexic muscle. Our results revealed the activation of a denervation-induced gene program that upregulates the transcription factor myogenin. Further studies showed that a myogenin-myostatin pathway promotes muscle atrophy in response to cancer cachexia. shRNA inhibition of myogenin or inhibition of myostatin through overexpression of its endogenous inhibitor follistatin prevented cancer cachexia-induced muscle atrophy in mice. Our findings uncover a molecular basis of cancer cachexia-induced muscle atrophy and highlight potential therapeutic targets for this disorder.
2024-07-12 | GSE272084 | GEO
Project description:Cancer cachexia is a prevalent and often fatal wasting condition that cannot be fully reversed with nutritional interventions. Muscle atrophy is a central component of the syndrome, but the mechanisms whereby cancer leads to skeletal muscle atrophy are not well understood. We performed single nucleus multi-omics on skeletal muscles from a mouse model of cancer cachexia and profiled the molecular changes in cachexic muscle. Our results revealed the activation of a denervation-induced gene program that upregulates the transcription factor myogenin. Further studies showed that a myogenin-myostatin pathway promotes muscle atrophy in response to cancer cachexia. shRNA inhibition of myogenin or inhibition of myostatin through overexpression of its endogenous inhibitor follistatin prevented cancer cachexia-induced muscle atrophy in mice. Our findings uncover a molecular basis of cancer cachexia-induced muscle atrophy and highlight potential therapeutic targets for this disorder.
2024-07-12 | GSE272083 | GEO
Project description:Skeletal muscle atrophy is a consequence of many diseases, environmental insults, inactivity, age and injury. Atrophy is characterized by active degradation and removal of contractile proteins and a reduction in fiber size. Animal models have been extensively used to identify pathways leading to atrophic conditions. Here we have used genome-wide expression profiling analysis and quantitative PCR to identify the molecular changes that occur in two clinically relevant animal mouse models of muscle atrophy, hindlimb casting and Achilles tendon laceration (tenotomy). Gastrocnemius muscle samples were collected 2, 7 and 14 days after insult. The total amount of muscle loss as measured by wet weight and muscle fiber size was equivalent between models, although tenotomy resulted in a more rapid induction of muscle atrophy. Furthermore, tentomy resulted in the regulation of significantly more mRNA transcripts then casting. Analysis of the regulated genes and pathways suggest that the mechanism of atrophy is distinct between these models. The degradation following casting appears ubiquitin-proteasome-mediated while degradation following tenotomy appears lysosomal and matrix-metalloproteinase (MMP)-mediated. This data suggests that there are multiple mechanisms leading to muscle atrophy and that specific therapeutic agents may be necessary to combat the atrophy seen under different conditions. Muscle atrophy was induced through two methods; unloading induced by tendon laceration (Tenotomy) and immobilization induced by hindlimb casting (Casting). For the tenotomy, eight week old male C57/B6 mice were anesthetized by ether inhalation and subsequent intramuscular injection of ketamine-xylazine (0.1 ml/g). The right Achilles tendon just proximal to the calcaneus was severed with a sterile scalpel. The mice were allowed to recover and move freely about their cage. An additional cohort of animals was sham operated (Sham) which involved isolation and manipulation of the Achilles tendon without laceration. For the casting, the right hindlimbs of eight week old male C57Bl/6 mice were immobilized through casting. After 2, 7 or 14 days, animals were sacrificed and the left and right gastrocnemius muscles were carefully removed, flash frozen in liquid nitrogen, and stored at -80°C for further processing. The left untreated legs served as controls. A group of naïve animals that received no treatment or manipulation was included as an additional control. Each group consisted of between 5 and 10 samples for a total of 111 individual samples.
2011-10-24 | E-GEOD-25908 | biostudies-arrayexpress
Project description:Notch signaling plays essential roles in maintenance of muscle stem cell pool. We found that Notch2, but not Notch1 and Notch3, is expressed in fully differentiated myofibers. To study the specific role of Notch2 in adult myofibers, we generated muscle-specific Notch2-knockout mice. Here, we showed that muscle-specific Notch2 deficiency prevented muscle atrophy induced by hindlimb unloading and diabetes millitus. RNA sequencing analysis revealed that the loss of Notch2 gene in myofibers inhibited gene responses to unloading and diabetes. Especially, several FoxO-target genes and atrogenes were upregulated in wildtype muscles but not in Notch2-deficient muscles by unloading and diabetes. Thus, our characterization of muscle-specific Notch2-knockout mice indicates that Notch2 acts as a regulatory factor of skeletal muscle plasticity and could be a therapeutic target of muscle atrophy.
2022-01-07 | GSE161693 | GEO
Project description:Immune checkpoint inhibitors (ICIs) can induce immune-related adverse events (irAEs) due to an overly activated immune system, despite their anti-cancer effects. Here, we observe that ICI treatment is associated with body weight loss in cancer patients. Similarly, anti-PD-L1 exacerbates muscle wasting in cancer cachexia (CAC) mice, despite its tumor suppressive effects, suggesting muscle atrophy as a potential irAE. Notably, CD8+ T cells accumulate in the skeletal muscle of CAC mice, which is amplified by anti-PD-L1. These CD8+ T cells directly promote muscle wasting, but their depletion effectively prevents cachectic features in CAC mice. We identify cathepsin L (CTSL) as an inter-organ target capable of suppressing both cancer and muscle wasting, particularly that driven by CD8+ T cells. Indeed, CTSL blockade effectively mitigates muscle wasting and further enhances the anti-tumor activity of anti-PD-L1. Thus, CTSL represents a dual therapeutic target for both cancer and cachexia, offering the potential to prevent muscle-related irAE when combined with ICIs.
2024-10-01 | GSE278013 | GEO
Project description:Immune checkpoint inhibitors (ICIs) can induce immune-related adverse events (irAEs) due to an overly activated immune system, despite their anti-cancer effects. Here, we observe that ICI treatment is associated with body weight loss in cancer patients. Similarly, anti-PD-L1 exacerbates muscle wasting in cancer cachexia (CAC) mice, despite its tumor suppressive effects, suggesting muscle atrophy as a potential irAE. Notably, CD8+ T cells accumulate in the skeletal muscle of CAC mice, which is amplified by anti-PD-L1. These CD8+ T cells directly promote muscle wasting, but their depletion effectively prevents cachectic features in CAC mice. We identify cathepsin L (CTSL) as an inter-organ target capable of suppressing both cancer and muscle wasting, particularly that driven by CD8+ T cells. Indeed, CTSL blockade effectively mitigates muscle wasting and further enhances the anti-tumor activity of anti-PD-L1. Thus, CTSL represents a dual therapeutic target for both cancer and cachexia, offering the potential to prevent muscle-related irAE when combined with ICIs.
2024-11-15 | GSE278765 | GEO
Project description:Immune checkpoint inhibitors (ICIs) can induce immune-related adverse events (irAEs) due to an overly activated immune system, despite their anti-cancer effects. Here, we observe that ICI treatment is associated with body weight loss in cancer patients. Similarly, anti-PD-L1 exacerbates muscle wasting in cancer cachexia (CAC) mice, despite its tumor suppressive effects, suggesting muscle atrophy as a potential irAE. Notably, CD8+ T cells accumulate in the skeletal muscle of CAC mice, which is amplified by anti-PD-L1. These CD8+ T cells directly promote muscle wasting, but their depletion effectively prevents cachectic features in CAC mice. We identify cathepsin L (CTSL) as an inter-organ target capable of suppressing both cancer and muscle wasting, particularly that driven by CD8+ T cells. Indeed, CTSL blockade effectively mitigates muscle wasting and further enhances the anti-tumor activity of anti-PD-L1. Thus, CTSL represents a dual therapeutic target for both cancer and cachexia, offering the potential to prevent muscle-related irAE when combined with ICIs.
2024-10-08 | GSE278396 | GEO