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Christopher M. Adams - One of the best experts on this subject based on the ideXlab platform.

  • identification and small molecule inhibition of an activating transcription factor 4 atf4 dependent pathway to age related skeletal muscle weakness and atrophy
    Journal of Biological Chemistry, 2015
    Co-Authors: Scott M. Ebert, Michael C Dyle, Jason M Dierdorff, Steven A Bullard, Daryl J Murry, Kale S Bongers, Vitor A Lira, David K Meyerholz, John J Talley, Christopher M. Adams
    Abstract:

    Aging reduces skeletal muscle mass and strength, but the underlying molecular mechanisms remain elusive. Here, we used mouse models to investigate molecular mechanisms of age-related skeletal muscle weakness and atrophy as well as new potential interventions for these conditions. We identified two small molecules that significantly reduce age-related deficits in skeletal muscle strength, quality, and mass: ursolic acid (a pentacyclic triterpenoid found in apples) and Tomatidine (a steroidal alkaloid derived from green tomatoes). Because small molecule inhibitors can sometimes provide mechanistic insight into disease processes, we used ursolic acid and Tomatidine to investigate the pathogenesis of age-related muscle weakness and atrophy. We found that ursolic acid and Tomatidine generate hundreds of small positive and negative changes in mRNA levels in aged skeletal muscle, and the mRNA expression signatures of the two compounds are remarkably similar. Interestingly, a subset of the mRNAs repressed by ursolic acid and Tomatidine in aged muscle are positively regulated by activating transcription factor 4 (ATF4). Based on this finding, we investigated ATF4 as a potential mediator of age-related muscle weakness and atrophy. We found that a targeted reduction in skeletal muscle ATF4 expression reduces age-related deficits in skeletal muscle strength, quality, and mass, similar to ursolic acid and Tomatidine. These results elucidate ATF4 as a critical mediator of age-related muscle weakness and atrophy. In addition, these results identify ursolic acid and Tomatidine as potential agents and/or lead compounds for reducing ATF4 activity, weakness, and atrophy in aged skeletal muscle.

  • systems based discovery of Tomatidine as a natural small molecule inhibitor of skeletal muscle atrophy
    Journal of Biological Chemistry, 2014
    Co-Authors: Michael C Dyle, Kale Stephen Bongers, Steven D Kunkel, Jason M Dierdorff, Daniel P Cook, Scott M. Ebert, Stephen A Bullard, Christopher M. Adams
    Abstract:

    Skeletal muscle atrophy is a common and debilitating condition that lacks an effective therapy. To address this problem, we used a systems-based discovery strategy to search for a small molecule whose mRNA expression signature negatively correlates to mRNA expression signatures of human skeletal muscle atrophy. This strategy identified a natural small molecule from tomato plants, Tomatidine. Using cultured skeletal myotubes from both humans and mice, we found that Tomatidine stimulated mTORC1 signaling and anabolism, leading to accumulation of protein and mitochondria, and ultimately, cell growth. Furthermore, in mice, Tomatidine increased skeletal muscle mTORC1 signaling, reduced skeletal muscle atrophy, enhanced recovery from skeletal muscle atrophy, stimulated skeletal muscle hypertrophy, and increased strength and exercise capacity. Collectively, these results identify Tomatidine as a novel small molecule inhibitor of muscle atrophy. Tomatidine may have utility as a therapeutic agent or lead compound for skeletal muscle atrophy.

Dae-kyu Song - One of the best experts on this subject based on the ideXlab platform.

  • Tomatidine inhibits tumor necrosis factor-α-induced apoptosis in C_2C_12 myoblasts via ameliorating endoplasmic reticulum stress
    Molecular and Cellular Biochemistry, 2018
    Co-Authors: Seung-eun Song, Su-kyung Shin, Seung-soon Im, Taeg-kyu Kwon, Dae-kyu Song
    Abstract:

    In this study, we examined the effect of Tomatidine on tumor necrosis factor (TNF)-α-induced apoptosis in C_2C_12 myoblasts. TNF-α treatment increased cleaved caspase 3 and cleaved poly (ADP-ribose) polymerase (PARP) protein levels in a dose- and time-dependent manner. Pretreatment of cells with 10 μM Tomatidine prevented TNF-α-induced apoptosis, caspase 3 cleavage, and PARP cleavage. Cells were treated with 100 ng/mL TNF-α for 24 h, and flow cytometry was utilized to assess apoptosis using annexin-V and 7-aminoactinomycin D. TNF-α up-regulated activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) expression. This effect was suppressed by pretreatment with Tomatidine. Pretreatment with 4-phenylbutyric acid (a chemical chaperone) also inhibited TNF-α-induced cleavage of caspase 3 and PARP and up-regulation of ATF4 and CHOP expression. In addition, Tomatidine-mediated inhibition of phosphorylation of c-Jun amino terminal kinase (JNK) attenuated TNF-α-induced cleavage of PARP and caspase 3. However, Tomatidine did not affect NF-κB activation in TNF-α-treated C_2C_12 myoblast cells. Taken together, the present study demonstrates that Tomatidine attenuates TNF-α-induced apoptosis through down-regulation of CHOP expression and inhibition of JNK activation.

  • Tomatidine inhibits tumor necrosis factor-α-induced apoptosis in C_2C_12 myoblasts via ameliorating endoplasmic reticulum stress
    Molecular and Cellular Biochemistry, 2018
    Co-Authors: Seung-eun Song, Su-kyung Shin, Taeg-kyu Kwon, Hyun-woo Cho, Jae-hoon Bae, Seon Min Woo, Dae-kyu Song
    Abstract:

    In this study, we examined the effect of Tomatidine on tumor necrosis factor (TNF)-α-induced apoptosis in C_2C_12 myoblasts. TNF-α treatment increased cleaved caspase 3 and cleaved poly (ADP-ribose) polymerase (PARP) protein levels in a dose- and time-dependent manner. Pretreatment of cells with 10 μM Tomatidine prevented TNF-α-induced apoptosis, caspase 3 cleavage, and PARP cleavage. Cells were treated with 100 ng/mL TNF-α for 24 h, and flow cytometry was utilized to assess apoptosis using annexin-V and 7-aminoactinomycin D. TNF-α up-regulated activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) expression. This effect was suppressed by pretreatment with Tomatidine. Pretreatment with 4-phenylbutyric acid (a chemical chaperone) also inhibited TNF-α-induced cleavage of caspase 3 and PARP and up-regulation of ATF4 and CHOP expression. In addition, Tomatidine-mediated inhibition of phosphorylation of c-Jun amino terminal kinase (JNK) attenuated TNF-α-induced cleavage of PARP and caspase 3. However, Tomatidine did not affect NF-κB activation in TNF-α-treated C_2C_12 myoblast cells. Taken together, the present study demonstrates that Tomatidine attenuates TNF-α-induced apoptosis through down-regulation of CHOP expression and inhibition of JNK activation.

  • Tomatidine inhibits tumor necrosis factor-α-induced apoptosis in C2C12 myoblasts via ameliorating endoplasmic reticulum stress.
    Molecular and Cellular Biochemistry, 2017
    Co-Authors: Seung-eun Song, Su-kyung Shin, Taeg-kyu Kwon, Hyun-woo Cho, Jae-hoon Bae, Seon Min Woo, Dae-kyu Song
    Abstract:

    In this study, we examined the effect of Tomatidine on tumor necrosis factor (TNF)-α-induced apoptosis in C2C12 myoblasts. TNF-α treatment increased cleaved caspase 3 and cleaved poly (ADP-ribose) polymerase (PARP) protein levels in a dose- and time-dependent manner. Pretreatment of cells with 10 μM Tomatidine prevented TNF-α-induced apoptosis, caspase 3 cleavage, and PARP cleavage. Cells were treated with 100 ng/mL TNF-α for 24 h, and flow cytometry was utilized to assess apoptosis using annexin-V and 7-aminoactinomycin D. TNF-α up-regulated activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) expression. This effect was suppressed by pretreatment with Tomatidine. Pretreatment with 4-phenylbutyric acid (a chemical chaperone) also inhibited TNF-α-induced cleavage of caspase 3 and PARP and up-regulation of ATF4 and CHOP expression. In addition, Tomatidine-mediated inhibition of phosphorylation of c-Jun amino terminal kinase (JNK) attenuated TNF-α-induced cleavage of PARP and caspase 3. However, Tomatidine did not affect NF-κB activation in TNF-α-treated C2C12 myoblast cells. Taken together, the present study demonstrates that Tomatidine attenuates TNF-α-induced apoptosis through down-regulation of CHOP expression and inhibition of JNK activation.

Michael C Dyle - One of the best experts on this subject based on the ideXlab platform.

  • identification and small molecule inhibition of an activating transcription factor 4 atf4 dependent pathway to age related skeletal muscle weakness and atrophy
    Journal of Biological Chemistry, 2015
    Co-Authors: Scott M. Ebert, Michael C Dyle, Jason M Dierdorff, Steven A Bullard, Daryl J Murry, Kale S Bongers, Vitor A Lira, David K Meyerholz, John J Talley, Christopher M. Adams
    Abstract:

    Aging reduces skeletal muscle mass and strength, but the underlying molecular mechanisms remain elusive. Here, we used mouse models to investigate molecular mechanisms of age-related skeletal muscle weakness and atrophy as well as new potential interventions for these conditions. We identified two small molecules that significantly reduce age-related deficits in skeletal muscle strength, quality, and mass: ursolic acid (a pentacyclic triterpenoid found in apples) and Tomatidine (a steroidal alkaloid derived from green tomatoes). Because small molecule inhibitors can sometimes provide mechanistic insight into disease processes, we used ursolic acid and Tomatidine to investigate the pathogenesis of age-related muscle weakness and atrophy. We found that ursolic acid and Tomatidine generate hundreds of small positive and negative changes in mRNA levels in aged skeletal muscle, and the mRNA expression signatures of the two compounds are remarkably similar. Interestingly, a subset of the mRNAs repressed by ursolic acid and Tomatidine in aged muscle are positively regulated by activating transcription factor 4 (ATF4). Based on this finding, we investigated ATF4 as a potential mediator of age-related muscle weakness and atrophy. We found that a targeted reduction in skeletal muscle ATF4 expression reduces age-related deficits in skeletal muscle strength, quality, and mass, similar to ursolic acid and Tomatidine. These results elucidate ATF4 as a critical mediator of age-related muscle weakness and atrophy. In addition, these results identify ursolic acid and Tomatidine as potential agents and/or lead compounds for reducing ATF4 activity, weakness, and atrophy in aged skeletal muscle.

  • systems based discovery of Tomatidine as a natural small molecule inhibitor of skeletal muscle atrophy
    Journal of Biological Chemistry, 2014
    Co-Authors: Michael C Dyle, Kale Stephen Bongers, Steven D Kunkel, Jason M Dierdorff, Daniel P Cook, Scott M. Ebert, Stephen A Bullard, Christopher M. Adams
    Abstract:

    Skeletal muscle atrophy is a common and debilitating condition that lacks an effective therapy. To address this problem, we used a systems-based discovery strategy to search for a small molecule whose mRNA expression signature negatively correlates to mRNA expression signatures of human skeletal muscle atrophy. This strategy identified a natural small molecule from tomato plants, Tomatidine. Using cultured skeletal myotubes from both humans and mice, we found that Tomatidine stimulated mTORC1 signaling and anabolism, leading to accumulation of protein and mitochondria, and ultimately, cell growth. Furthermore, in mice, Tomatidine increased skeletal muscle mTORC1 signaling, reduced skeletal muscle atrophy, enhanced recovery from skeletal muscle atrophy, stimulated skeletal muscle hypertrophy, and increased strength and exercise capacity. Collectively, these results identify Tomatidine as a novel small molecule inhibitor of muscle atrophy. Tomatidine may have utility as a therapeutic agent or lead compound for skeletal muscle atrophy.

Scott M. Ebert - One of the best experts on this subject based on the ideXlab platform.

  • identification and small molecule inhibition of an activating transcription factor 4 atf4 dependent pathway to age related skeletal muscle weakness and atrophy
    Journal of Biological Chemistry, 2015
    Co-Authors: Scott M. Ebert, Michael C Dyle, Jason M Dierdorff, Steven A Bullard, Daryl J Murry, Kale S Bongers, Vitor A Lira, David K Meyerholz, John J Talley, Christopher M. Adams
    Abstract:

    Aging reduces skeletal muscle mass and strength, but the underlying molecular mechanisms remain elusive. Here, we used mouse models to investigate molecular mechanisms of age-related skeletal muscle weakness and atrophy as well as new potential interventions for these conditions. We identified two small molecules that significantly reduce age-related deficits in skeletal muscle strength, quality, and mass: ursolic acid (a pentacyclic triterpenoid found in apples) and Tomatidine (a steroidal alkaloid derived from green tomatoes). Because small molecule inhibitors can sometimes provide mechanistic insight into disease processes, we used ursolic acid and Tomatidine to investigate the pathogenesis of age-related muscle weakness and atrophy. We found that ursolic acid and Tomatidine generate hundreds of small positive and negative changes in mRNA levels in aged skeletal muscle, and the mRNA expression signatures of the two compounds are remarkably similar. Interestingly, a subset of the mRNAs repressed by ursolic acid and Tomatidine in aged muscle are positively regulated by activating transcription factor 4 (ATF4). Based on this finding, we investigated ATF4 as a potential mediator of age-related muscle weakness and atrophy. We found that a targeted reduction in skeletal muscle ATF4 expression reduces age-related deficits in skeletal muscle strength, quality, and mass, similar to ursolic acid and Tomatidine. These results elucidate ATF4 as a critical mediator of age-related muscle weakness and atrophy. In addition, these results identify ursolic acid and Tomatidine as potential agents and/or lead compounds for reducing ATF4 activity, weakness, and atrophy in aged skeletal muscle.

  • systems based discovery of Tomatidine as a natural small molecule inhibitor of skeletal muscle atrophy
    Journal of Biological Chemistry, 2014
    Co-Authors: Michael C Dyle, Kale Stephen Bongers, Steven D Kunkel, Jason M Dierdorff, Daniel P Cook, Scott M. Ebert, Stephen A Bullard, Christopher M. Adams
    Abstract:

    Skeletal muscle atrophy is a common and debilitating condition that lacks an effective therapy. To address this problem, we used a systems-based discovery strategy to search for a small molecule whose mRNA expression signature negatively correlates to mRNA expression signatures of human skeletal muscle atrophy. This strategy identified a natural small molecule from tomato plants, Tomatidine. Using cultured skeletal myotubes from both humans and mice, we found that Tomatidine stimulated mTORC1 signaling and anabolism, leading to accumulation of protein and mitochondria, and ultimately, cell growth. Furthermore, in mice, Tomatidine increased skeletal muscle mTORC1 signaling, reduced skeletal muscle atrophy, enhanced recovery from skeletal muscle atrophy, stimulated skeletal muscle hypertrophy, and increased strength and exercise capacity. Collectively, these results identify Tomatidine as a novel small molecule inhibitor of muscle atrophy. Tomatidine may have utility as a therapeutic agent or lead compound for skeletal muscle atrophy.

Jason M Dierdorff - One of the best experts on this subject based on the ideXlab platform.

  • identification and small molecule inhibition of an activating transcription factor 4 atf4 dependent pathway to age related skeletal muscle weakness and atrophy
    Journal of Biological Chemistry, 2015
    Co-Authors: Scott M. Ebert, Michael C Dyle, Jason M Dierdorff, Steven A Bullard, Daryl J Murry, Kale S Bongers, Vitor A Lira, David K Meyerholz, John J Talley, Christopher M. Adams
    Abstract:

    Aging reduces skeletal muscle mass and strength, but the underlying molecular mechanisms remain elusive. Here, we used mouse models to investigate molecular mechanisms of age-related skeletal muscle weakness and atrophy as well as new potential interventions for these conditions. We identified two small molecules that significantly reduce age-related deficits in skeletal muscle strength, quality, and mass: ursolic acid (a pentacyclic triterpenoid found in apples) and Tomatidine (a steroidal alkaloid derived from green tomatoes). Because small molecule inhibitors can sometimes provide mechanistic insight into disease processes, we used ursolic acid and Tomatidine to investigate the pathogenesis of age-related muscle weakness and atrophy. We found that ursolic acid and Tomatidine generate hundreds of small positive and negative changes in mRNA levels in aged skeletal muscle, and the mRNA expression signatures of the two compounds are remarkably similar. Interestingly, a subset of the mRNAs repressed by ursolic acid and Tomatidine in aged muscle are positively regulated by activating transcription factor 4 (ATF4). Based on this finding, we investigated ATF4 as a potential mediator of age-related muscle weakness and atrophy. We found that a targeted reduction in skeletal muscle ATF4 expression reduces age-related deficits in skeletal muscle strength, quality, and mass, similar to ursolic acid and Tomatidine. These results elucidate ATF4 as a critical mediator of age-related muscle weakness and atrophy. In addition, these results identify ursolic acid and Tomatidine as potential agents and/or lead compounds for reducing ATF4 activity, weakness, and atrophy in aged skeletal muscle.

  • systems based discovery of Tomatidine as a natural small molecule inhibitor of skeletal muscle atrophy
    Journal of Biological Chemistry, 2014
    Co-Authors: Michael C Dyle, Kale Stephen Bongers, Steven D Kunkel, Jason M Dierdorff, Daniel P Cook, Scott M. Ebert, Stephen A Bullard, Christopher M. Adams
    Abstract:

    Skeletal muscle atrophy is a common and debilitating condition that lacks an effective therapy. To address this problem, we used a systems-based discovery strategy to search for a small molecule whose mRNA expression signature negatively correlates to mRNA expression signatures of human skeletal muscle atrophy. This strategy identified a natural small molecule from tomato plants, Tomatidine. Using cultured skeletal myotubes from both humans and mice, we found that Tomatidine stimulated mTORC1 signaling and anabolism, leading to accumulation of protein and mitochondria, and ultimately, cell growth. Furthermore, in mice, Tomatidine increased skeletal muscle mTORC1 signaling, reduced skeletal muscle atrophy, enhanced recovery from skeletal muscle atrophy, stimulated skeletal muscle hypertrophy, and increased strength and exercise capacity. Collectively, these results identify Tomatidine as a novel small molecule inhibitor of muscle atrophy. Tomatidine may have utility as a therapeutic agent or lead compound for skeletal muscle atrophy.