Alexis Boulinguiez, Jamila Dhiab, Barbara Crisol, Laura Muraine, Ludovic Gaut, Corentin Rouxel, Justine Flaire, Hadidja-Rose Mouigni, Mégane Lemaitre, Benoit Giroux, Lucie Audoux, Benjamin SaintPierre, Arnaud Ferry, Vincent Mouly, Gillian Butler-Browne, Elisa Negroni, Alberto Malerba, Capucine Trollet
Background: Exercise is widely considered to have beneficial impact on skeletal muscle aging. In addition, there are also several studies demonstrating a positive effect of exercise on muscular dystrophies. Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominant inherited neuromuscular disorder caused by mutations in the PAPBN1 gene. These mutations consist in short (1-8) and meiotically stable GCN trinucleotide repeat expansions in its coding region responsible for the formation of PAPBN1 intranuclear aggregates. This study aims to characterize the effects of two types of chronic exercise, resistance and endurance, on the OPMD skeletal muscle phenotype using a relevant murine model of OPMD.
Methods: In this study, we tested two protocols of exercise. In the first, based on endurance exercise, FvB (wild-type) and A17 (OPMD) mice underwent a 6-week-long motorized treadmill protocol consisting in three sessions per week of running 20 cm/s for 20 min. In the second protocol, based on resistance exercise generated by chronic mechanical overload (OVL), surgical removal of gastrocnemius and soleus muscles was performed, inducing hypertrophy of the plantaris muscle. In both types of exercise, muscles of A17 and FvB mice were compared with those of respective sedentary mice. For all the groups, force measurement, muscle histology, and molecular analyses were conducted.
Results: Following the endurance exercise protocol, we did not observe any major changes in the muscle physiological parameters, but an increase in the number of PABPN1 intranuclear aggregates in both tibialis anterior (+24%, **P = 0.0026) and gastrocnemius (+18%, ****P < 0.0001) as well as enhanced collagen deposition (+20%, **P = 0.0064 in the tibialis anterior; +35%, **P = 0.0042 in the gastrocnemius) in the exercised A17 OPMD mice. In the supraphysiological resistance overload protocol, we also observed an increased collagen deposition (×2, ****P < 0.0001) in the plantaris muscle of A17 OPMD mice which was associated with larger muscle mass (×2, ****P < 0.0001) and fibre cross sectional area (×2, ***P = 0.0007) and increased absolute maximal force (×2, ****P < 0.0001) as well as a reduction in PABPN1 aggregate number (-16%, ****P < 0.0001).
Conclusions: Running exercise and mechanical overload led to very different outcome in skeletal muscles of A17 mice. Both types of exercise enhanced collagen deposition but while the running protocol increased aggregates, the OVL reduced them. More importantly OVL reversed muscle atrophy and maximal force in the A17 mice. Our study performed in a relevant model gives an indication of the effect of different types of exercise on OPMD muscle which should be further evaluated in humans for future recommendations as a part of the lifestyle of individuals with OPMD.
{"title":"Different outcomes of endurance and resistance exercise in skeletal muscles of Oculopharyngeal muscular dystrophy.","authors":"Alexis Boulinguiez, Jamila Dhiab, Barbara Crisol, Laura Muraine, Ludovic Gaut, Corentin Rouxel, Justine Flaire, Hadidja-Rose Mouigni, Mégane Lemaitre, Benoit Giroux, Lucie Audoux, Benjamin SaintPierre, Arnaud Ferry, Vincent Mouly, Gillian Butler-Browne, Elisa Negroni, Alberto Malerba, Capucine Trollet","doi":"10.1002/jcsm.13546","DOIUrl":"https://doi.org/10.1002/jcsm.13546","url":null,"abstract":"<p><strong>Background: </strong>Exercise is widely considered to have beneficial impact on skeletal muscle aging. In addition, there are also several studies demonstrating a positive effect of exercise on muscular dystrophies. Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominant inherited neuromuscular disorder caused by mutations in the PAPBN1 gene. These mutations consist in short (1-8) and meiotically stable GCN trinucleotide repeat expansions in its coding region responsible for the formation of PAPBN1 intranuclear aggregates. This study aims to characterize the effects of two types of chronic exercise, resistance and endurance, on the OPMD skeletal muscle phenotype using a relevant murine model of OPMD.</p><p><strong>Methods: </strong>In this study, we tested two protocols of exercise. In the first, based on endurance exercise, FvB (wild-type) and A17 (OPMD) mice underwent a 6-week-long motorized treadmill protocol consisting in three sessions per week of running 20 cm/s for 20 min. In the second protocol, based on resistance exercise generated by chronic mechanical overload (OVL), surgical removal of gastrocnemius and soleus muscles was performed, inducing hypertrophy of the plantaris muscle. In both types of exercise, muscles of A17 and FvB mice were compared with those of respective sedentary mice. For all the groups, force measurement, muscle histology, and molecular analyses were conducted.</p><p><strong>Results: </strong>Following the endurance exercise protocol, we did not observe any major changes in the muscle physiological parameters, but an increase in the number of PABPN1 intranuclear aggregates in both tibialis anterior (+24%, **P = 0.0026) and gastrocnemius (+18%, ****P < 0.0001) as well as enhanced collagen deposition (+20%, **P = 0.0064 in the tibialis anterior; +35%, **P = 0.0042 in the gastrocnemius) in the exercised A17 OPMD mice. In the supraphysiological resistance overload protocol, we also observed an increased collagen deposition (×2, ****P < 0.0001) in the plantaris muscle of A17 OPMD mice which was associated with larger muscle mass (×2, ****P < 0.0001) and fibre cross sectional area (×2, ***P = 0.0007) and increased absolute maximal force (×2, ****P < 0.0001) as well as a reduction in PABPN1 aggregate number (-16%, ****P < 0.0001).</p><p><strong>Conclusions: </strong>Running exercise and mechanical overload led to very different outcome in skeletal muscles of A17 mice. Both types of exercise enhanced collagen deposition but while the running protocol increased aggregates, the OVL reduced them. More importantly OVL reversed muscle atrophy and maximal force in the A17 mice. Our study performed in a relevant model gives an indication of the effect of different types of exercise on OPMD muscle which should be further evaluated in humans for future recommendations as a part of the lifestyle of individuals with OPMD.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":null,"pages":null},"PeriodicalIF":8.9,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141900293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zongliang Lu, Li Wang, Zhenyu Huo, Na Li, Ning Tong, Feifei Chong, Jie Liu, Yaowen Zhang, Hongxia Xu
Background: Cancer cachexia-induced skeletal muscle fibrosis (SMF) impairs muscle regeneration, alters the muscle structure and function, reduces the efficacy of anticancer drugs, diminishes the patient's quality of life and shortens overall survival. RUNX family transcription factor 2 (Runx2), a transcription factor, and collagen type I alpha 1 chain (COL1A1), the principal constituent of SMF, have been linked previously, with Runx2 shown to directly modulate COL1A1 mRNA levels. l-Carnitine, a marker of cancer cachexia, can alleviate fibrosis in liver and kidney models; however, its role in cancer cachexia-associated fibrosis and the involvement of Runx2 in the process remain unexplored.
Methods: Female C57 mice (48 weeks old) were inoculated subcutaneously with MC38 cells to establish a cancer cachexia model. A 5 mg/kg dose of l-carnitine or an equivalent volume of water was administered for 14 days via oral gavage, followed by assessments of muscle function (grip strength) and fibrosis. To elucidate the interplay between the deltex E3 ubiquitin ligase 3L(DTX3L)/Runx2/COL1A1 axis and fibrosis in transforming growth factor beta 1-stimulated NIH/3T3 cells, a suite of molecular techniques, including quantitative real-time PCR, western blot analysis, co-immunoprecipitation, molecular docking, immunofluorescence and Duolink assays, were used. The relevance of the DTX3L/Runx2/COL1A1 axis in the gastrocnemius was also explored in the in vivo model.
Results: l-Carnitine supplementation reduced cancer cachexia-induced declines in grip strength (>88.2%, P < 0.05) and the collagen fibre area within the gastrocnemius (>57.9%, P < 0.05). At the 5 mg/kg dose, l-carnitine also suppressed COL1A1 and alpha-smooth muscle actin (α-SMA) protein expression, which are markers of SMF and myofibroblasts. Analyses of the TRRUST database indicated that Runx2 regulates both COL1A1 and COL1A2. In vitro, l-carnitine diminished Runx2 protein levels and promoted its ubiquitination. Overexpression of Runx2 abolished the effects of l-carnitine on COL1A1 and α-SMA. Co-immunoprecipitation, molecular docking, immunofluorescence and Duolink assays confirmed an interaction between DTX3L and Runx2, with l-carnitine enhancing this interaction to promote Runx2 ubiquitination. l-Carnitine supplementation restored DTX3L levels to those observed under non-cachectic conditions, both in vitro and in vivo. Knockdown of DTX3L abolished the effects of l-carnitine on Runx2, COL1A1 and α-SMA in vitro. The expression of DTX3L was negatively correlated with the levels of Runx2 and COL1A1 in untreated NIH/3T3 cells.
Conclusions: This study revealed a previously unrecognized link between Runx2 and DTX3L in SMF and demonstrated that l-carnitine exerted a significant therapeutic impact on cancer cachexia-associated SMF, potentially through the upregulation of DTX3L.
{"title":"l-Carnitine relieves cachexia-related skeletal muscle fibrosis by inducing deltex E3 ubiquitin ligase 3L to negatively regulate the Runx2/COL1A1 axis.","authors":"Zongliang Lu, Li Wang, Zhenyu Huo, Na Li, Ning Tong, Feifei Chong, Jie Liu, Yaowen Zhang, Hongxia Xu","doi":"10.1002/jcsm.13544","DOIUrl":"https://doi.org/10.1002/jcsm.13544","url":null,"abstract":"<p><strong>Background: </strong>Cancer cachexia-induced skeletal muscle fibrosis (SMF) impairs muscle regeneration, alters the muscle structure and function, reduces the efficacy of anticancer drugs, diminishes the patient's quality of life and shortens overall survival. RUNX family transcription factor 2 (Runx2), a transcription factor, and collagen type I alpha 1 chain (COL1A1), the principal constituent of SMF, have been linked previously, with Runx2 shown to directly modulate COL1A1 mRNA levels. l-Carnitine, a marker of cancer cachexia, can alleviate fibrosis in liver and kidney models; however, its role in cancer cachexia-associated fibrosis and the involvement of Runx2 in the process remain unexplored.</p><p><strong>Methods: </strong>Female C57 mice (48 weeks old) were inoculated subcutaneously with MC38 cells to establish a cancer cachexia model. A 5 mg/kg dose of l-carnitine or an equivalent volume of water was administered for 14 days via oral gavage, followed by assessments of muscle function (grip strength) and fibrosis. To elucidate the interplay between the deltex E3 ubiquitin ligase 3L(DTX3L)/Runx2/COL1A1 axis and fibrosis in transforming growth factor beta 1-stimulated NIH/3T3 cells, a suite of molecular techniques, including quantitative real-time PCR, western blot analysis, co-immunoprecipitation, molecular docking, immunofluorescence and Duolink assays, were used. The relevance of the DTX3L/Runx2/COL1A1 axis in the gastrocnemius was also explored in the in vivo model.</p><p><strong>Results: </strong>l-Carnitine supplementation reduced cancer cachexia-induced declines in grip strength (>88.2%, P < 0.05) and the collagen fibre area within the gastrocnemius (>57.9%, P < 0.05). At the 5 mg/kg dose, l-carnitine also suppressed COL1A1 and alpha-smooth muscle actin (α-SMA) protein expression, which are markers of SMF and myofibroblasts. Analyses of the TRRUST database indicated that Runx2 regulates both COL1A1 and COL1A2. In vitro, l-carnitine diminished Runx2 protein levels and promoted its ubiquitination. Overexpression of Runx2 abolished the effects of l-carnitine on COL1A1 and α-SMA. Co-immunoprecipitation, molecular docking, immunofluorescence and Duolink assays confirmed an interaction between DTX3L and Runx2, with l-carnitine enhancing this interaction to promote Runx2 ubiquitination. l-Carnitine supplementation restored DTX3L levels to those observed under non-cachectic conditions, both in vitro and in vivo. Knockdown of DTX3L abolished the effects of l-carnitine on Runx2, COL1A1 and α-SMA in vitro. The expression of DTX3L was negatively correlated with the levels of Runx2 and COL1A1 in untreated NIH/3T3 cells.</p><p><strong>Conclusions: </strong>This study revealed a previously unrecognized link between Runx2 and DTX3L in SMF and demonstrated that l-carnitine exerted a significant therapeutic impact on cancer cachexia-associated SMF, potentially through the upregulation of DTX3L.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":null,"pages":null},"PeriodicalIF":8.9,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141873688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Richard F Dunne, Jeffrey Crawford, Karen E Smoyer, Thomas D McRae, Michelle I Rossulek, James H Revkin, Lisa C Tarasenko, Philip D Bonomi
Cancer-associated cachexia is a multifactorial wasting disorder characterized by anorexia, unintentional weight loss (skeletal muscle mass with or without loss of fat mass), progressive functional impairment, and poor prognosis. This systematic literature review (SLR) examined the relationship between cachexia and survival in patients with colorectal or pancreatic cancer in recent literature. The SLR was conducted following PRISMA guidelines. Embase® and PubMed were searched to identify articles published in English between 1 January 2016 and 10 October 2021 reporting survival in adults with cancer and cachexia or at risk of cachexia, defined by international consensus (IC) diagnostic criteria or a broader definition of any weight loss. Included publications were studies in ≥100 patients with colorectal or pancreatic cancer. Thirteen publications in patients with colorectal cancer and 13 with pancreatic cancer met eligibility criteria. Included studies were observational and primarily from Europe and the United States. Eleven studies (42%) reported cachexia using IC criteria and 15 (58%) reported any weight loss. An association between survival and cachexia or weight loss was assessed across studies using multivariate (n = 23) or univariate (n = 3) analyses and within each study across multiple weight loss categories. Cachexia/weight loss was associated with a statistically significantly poorer survival in at least one weight loss category in 16 of 23 studies that used multivariate analyses and in 1 of 3 studies (33%) that used univariate analyses. Of the 17 studies demonstrating a significant association, 9 were in patients with colorectal cancer and 8 were in patients with pancreatic cancer. Cachexia or weight loss was associated with significantly poorer survival in patients with colorectal or pancreatic cancer in nearly two-thirds of the studies. The classification of weight loss varied across and within studies (multiple categories were evaluated) and may have contributed to variability. Nonetheless, awareness of cachexia and routine assessment of weight change in clinical practice in patients with colorectal or pancreatic cancer could help inform prognosis and influence early disease management strategies.
{"title":"The mortality burden of cachexia or weight loss in patients with colorectal or pancreatic cancer: A systematic literature review.","authors":"Richard F Dunne, Jeffrey Crawford, Karen E Smoyer, Thomas D McRae, Michelle I Rossulek, James H Revkin, Lisa C Tarasenko, Philip D Bonomi","doi":"10.1002/jcsm.13510","DOIUrl":"https://doi.org/10.1002/jcsm.13510","url":null,"abstract":"<p><p>Cancer-associated cachexia is a multifactorial wasting disorder characterized by anorexia, unintentional weight loss (skeletal muscle mass with or without loss of fat mass), progressive functional impairment, and poor prognosis. This systematic literature review (SLR) examined the relationship between cachexia and survival in patients with colorectal or pancreatic cancer in recent literature. The SLR was conducted following PRISMA guidelines. Embase<sup>®</sup> and PubMed were searched to identify articles published in English between 1 January 2016 and 10 October 2021 reporting survival in adults with cancer and cachexia or at risk of cachexia, defined by international consensus (IC) diagnostic criteria or a broader definition of any weight loss. Included publications were studies in ≥100 patients with colorectal or pancreatic cancer. Thirteen publications in patients with colorectal cancer and 13 with pancreatic cancer met eligibility criteria. Included studies were observational and primarily from Europe and the United States. Eleven studies (42%) reported cachexia using IC criteria and 15 (58%) reported any weight loss. An association between survival and cachexia or weight loss was assessed across studies using multivariate (n = 23) or univariate (n = 3) analyses and within each study across multiple weight loss categories. Cachexia/weight loss was associated with a statistically significantly poorer survival in at least one weight loss category in 16 of 23 studies that used multivariate analyses and in 1 of 3 studies (33%) that used univariate analyses. Of the 17 studies demonstrating a significant association, 9 were in patients with colorectal cancer and 8 were in patients with pancreatic cancer. Cachexia or weight loss was associated with significantly poorer survival in patients with colorectal or pancreatic cancer in nearly two-thirds of the studies. The classification of weight loss varied across and within studies (multiple categories were evaluated) and may have contributed to variability. Nonetheless, awareness of cachexia and routine assessment of weight change in clinical practice in patients with colorectal or pancreatic cancer could help inform prognosis and influence early disease management strategies.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":null,"pages":null},"PeriodicalIF":8.9,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141877942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Previous data in humans suggest that extreme physical inactivity (EPI) affects iron metabolism differently between sexes. Our objective was to deepen the underlying mechanisms by studying rats of both sexes exposed to hindlimb unloading (HU), the reference experimental model mimicking EPI.
{"title":"Sex similarities and divergences in systemic and muscle iron metabolism adaptations to extreme physical inactivity in rats","authors":"Mathieu Horeau, Melissa Delalande, Martine Ropert, Patricia Leroyer, Brice Martin, Luz Orfila, Olivier Loréal, Frédéric Derbré","doi":"10.1002/jcsm.13547","DOIUrl":"https://doi.org/10.1002/jcsm.13547","url":null,"abstract":"Previous data in humans suggest that extreme physical inactivity (EPI) affects iron metabolism differently between sexes. Our objective was to deepen the underlying mechanisms by studying rats of both sexes exposed to hindlimb unloading (HU), the reference experimental model mimicking EPI.","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":null,"pages":null},"PeriodicalIF":8.9,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141754219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Intensive care unit-acquired weakness (ICU-AW) is a syndrome characterized by a long-term muscle weakness often observed in sepsis-surviving patients during the chronic phase. Although ICU-AW is independently associated with increased mortality, effective therapies have yet to be established. Programmed death-1 (PD-1) inhibitors have attracted attention as potential treatments for reversing immune exhaustion in sepsis; however, its impact on ICU-AW remains to be elucidated. Here, we study how PD-1 deficiency affects sepsis-induced skeletal muscle dysfunction in a preclinical sepsis model.
Methods: Chronic sepsis model was developed by treating wild-type (WT) and PD-1 knockout (KO) mice with caecal slurry, followed by resuscitation with antibiotics and saline. Mice were euthanized on days 15-17. Body weights, muscle weights, and limb muscle strengths were measured. Interleukin 13 (IL-13) and PD-1 expressions were examined by flow cytometry. Messenger RNA (mRNA) expressions of slow-twitch muscles were measured by reverse transcription and quantitative polymerase chain reaction (RT-qPCR). In an in vitro study, C2C12 myotubes were treated with lipopolysaccharide (LPS) and recombinant IL-13 followed by gene expression measurements.
Results: WT septic mice exhibited decreased muscle weight (quadriceps, P < 0.01; gastrocnemius, P < 0.05; and tibialis anterior, P < 0.01) and long-term muscle weakness (P < 0.0001), whereas PD-1 KO septic mice did not exhibit any reduction in muscle weights and strengths. Slow-twitch specific mRNAs, including myoglobin (Mb), troponin I type 1 (Tnni1), and myosin heavy chain 7 (Myh7) were decreased in WT skeletal muscle (Mb, P < 0.0001; Tnni1, P < 0.05; and Myh7, P < 0.05) after sepsis induction, but mRNA expressions of Tnni1 and Myh7 were increased in PD-1 KO septic mice (Mb, not significant; Tnni1, P < 0.0001; and Myh7, P < 0.05). Treatment of C2C12 myotube cells with LPS decreased the expression of slow-twitch mRNAs, which was restored by IL-13 (Mb, P < 0.0001; Tnni1, P < 0.001; and Myh7, P < 0.05). IL-13 production was significantly higher in ILC2s compared to T cells in skeletal muscle (P < 0.05). IL-13-producing ILC2s in skeletal muscle were examined and found to increase in PD-1 KO septic mice, compared with WT septic mice (P < 0.05). ILC2-derived IL-13 was increased by PD-1 KO septic mice and thought to protect the muscles from experimental ICU-AW.
Conclusions: Long-term muscle weakness in experimental ICU-AW was ameliorated in PD-1 KO mice. ILC2-derived IL-13 production in skeletal muscles was increased in PD-1 KO mice, thereby suggesting that IL-13 alleviates muscle weakness during sepsis. This study demonstrates the effects of PD-1 blockade in preserving muscle strength during sepsis through an increase in ILC2-derived IL-13 and may be an attractive therapeutic target for sepsis-induced ICU-AW.
{"title":"Roles of programmed death-1 and muscle innate lymphoid cell-derived interleukin 13 in sepsis-induced intensive care unit-acquired weakness.","authors":"Yuichi Akama, Eun Jeong Park, Naoko Satoh-Takayama, Atsushi Ito, Eiji Kawamoto, Arong Gaowa, Eri Matsuo, Satoshi Oikawa, Masafumi Saito, Shigeaki Inoue, Takayuki Akimoto, Kei Suzuki, Motomu Shimaoka","doi":"10.1002/jcsm.13548","DOIUrl":"https://doi.org/10.1002/jcsm.13548","url":null,"abstract":"<p><strong>Background: </strong>Intensive care unit-acquired weakness (ICU-AW) is a syndrome characterized by a long-term muscle weakness often observed in sepsis-surviving patients during the chronic phase. Although ICU-AW is independently associated with increased mortality, effective therapies have yet to be established. Programmed death-1 (PD-1) inhibitors have attracted attention as potential treatments for reversing immune exhaustion in sepsis; however, its impact on ICU-AW remains to be elucidated. Here, we study how PD-1 deficiency affects sepsis-induced skeletal muscle dysfunction in a preclinical sepsis model.</p><p><strong>Methods: </strong>Chronic sepsis model was developed by treating wild-type (WT) and PD-1 knockout (KO) mice with caecal slurry, followed by resuscitation with antibiotics and saline. Mice were euthanized on days 15-17. Body weights, muscle weights, and limb muscle strengths were measured. Interleukin 13 (IL-13) and PD-1 expressions were examined by flow cytometry. Messenger RNA (mRNA) expressions of slow-twitch muscles were measured by reverse transcription and quantitative polymerase chain reaction (RT-qPCR). In an in vitro study, C2C12 myotubes were treated with lipopolysaccharide (LPS) and recombinant IL-13 followed by gene expression measurements.</p><p><strong>Results: </strong>WT septic mice exhibited decreased muscle weight (quadriceps, P < 0.01; gastrocnemius, P < 0.05; and tibialis anterior, P < 0.01) and long-term muscle weakness (P < 0.0001), whereas PD-1 KO septic mice did not exhibit any reduction in muscle weights and strengths. Slow-twitch specific mRNAs, including myoglobin (Mb), troponin I type 1 (Tnni1), and myosin heavy chain 7 (Myh7) were decreased in WT skeletal muscle (Mb, P < 0.0001; Tnni1, P < 0.05; and Myh7, P < 0.05) after sepsis induction, but mRNA expressions of Tnni1 and Myh7 were increased in PD-1 KO septic mice (Mb, not significant; Tnni1, P < 0.0001; and Myh7, P < 0.05). Treatment of C2C12 myotube cells with LPS decreased the expression of slow-twitch mRNAs, which was restored by IL-13 (Mb, P < 0.0001; Tnni1, P < 0.001; and Myh7, P < 0.05). IL-13 production was significantly higher in ILC2s compared to T cells in skeletal muscle (P < 0.05). IL-13-producing ILC2s in skeletal muscle were examined and found to increase in PD-1 KO septic mice, compared with WT septic mice (P < 0.05). ILC2-derived IL-13 was increased by PD-1 KO septic mice and thought to protect the muscles from experimental ICU-AW.</p><p><strong>Conclusions: </strong>Long-term muscle weakness in experimental ICU-AW was ameliorated in PD-1 KO mice. ILC2-derived IL-13 production in skeletal muscles was increased in PD-1 KO mice, thereby suggesting that IL-13 alleviates muscle weakness during sepsis. This study demonstrates the effects of PD-1 blockade in preserving muscle strength during sepsis through an increase in ILC2-derived IL-13 and may be an attractive therapeutic target for sepsis-induced ICU-AW.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":null,"pages":null},"PeriodicalIF":8.9,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141625523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Despite extensive research on muscle loss in people living with HIV (PLWH), the prevalence and contributing factors specifically among middle-aged men remain unclear. This study aimed to determine the prevalence of low muscle mass within this demographic and to identify associated factors.
Methods: A total of 378 men living with HIV were enrolled in the study. They were classified into low muscle mass group if they displayed a skeletal muscle index (SMI) <7.00 kg/m2 or fell within the lowest quintile of SMI based on the criteria established by the Asian Working Group for Sarcopenia 2019.
Results: Out of the 378 men living with HIV enrolled, 351 had normal muscle mass, while 27 (7.1%) had low muscle mass. Antiretroviral drugs Zidovudine (AZT) (OR = 0.246, P = 0.022) and higher serum albumin levels (OR = 0.899, P = 0.026) were found to be protective factors against low muscle mass according to quintile grouping. Strong positive associations between SMI and body mass index (BMI), nutritional risk index (NRI), oedema index and fat-free mass index (FFMI) (R > 0.5, P < 0.001) were observed. In addition, both BMI (sensitivity = 0.741, specificity = 0.906) and NRI (sensitivity = 0.963, specificity = 0.601) had high sensitivity and specificity in diagnosing low muscle mass, with critical values of 19.85 and 114.177 for BMI and NRI, respectively. The oedema index was the most effective measure of body composition in detecting abnormal fluid retention with high sensitivity (92.6%) and moderate specificity (71.8%) in identifying individuals with low muscle mass. Notably, PLWH with low muscle mass participants had a significantly higher prevalence (92.6%) of a high oedema index compared with those with normal muscle mass (28.2%). This observation indicates that individuals with HIV who experience reduced muscle mass is commonly accompanied with abnormal fluid retention within the body.
Conclusions: Antiretroviral medication types, specifically Zidovudine, BMI and NRI can be independent risk factors for low muscle mass in men with HIV. These factors, along with BMI, could be used conveniently to predict low muscle mass. Furthermore, the association between the oedema index and muscle mass suggests that observing signs of oedema may indicate a risk of low muscle mass in PLWH.
{"title":"Factors associated with skeletal muscle mass in middle-aged men living with HIV.","authors":"Yide Xu, Dongdong Wang, Pei Chen, Bufeng Qi, Xiaoting Li, Chunfeng Xie, Jieshu Wu, Lin Li, Gu Gao, Shanshan Geng, Dandan Yang","doi":"10.1002/jcsm.13545","DOIUrl":"https://doi.org/10.1002/jcsm.13545","url":null,"abstract":"<p><strong>Background: </strong>Despite extensive research on muscle loss in people living with HIV (PLWH), the prevalence and contributing factors specifically among middle-aged men remain unclear. This study aimed to determine the prevalence of low muscle mass within this demographic and to identify associated factors.</p><p><strong>Methods: </strong>A total of 378 men living with HIV were enrolled in the study. They were classified into low muscle mass group if they displayed a skeletal muscle index (SMI) <7.00 kg/m<sup>2</sup> or fell within the lowest quintile of SMI based on the criteria established by the Asian Working Group for Sarcopenia 2019.</p><p><strong>Results: </strong>Out of the 378 men living with HIV enrolled, 351 had normal muscle mass, while 27 (7.1%) had low muscle mass. Antiretroviral drugs Zidovudine (AZT) (OR = 0.246, P = 0.022) and higher serum albumin levels (OR = 0.899, P = 0.026) were found to be protective factors against low muscle mass according to quintile grouping. Strong positive associations between SMI and body mass index (BMI), nutritional risk index (NRI), oedema index and fat-free mass index (FFMI) (R > 0.5, P < 0.001) were observed. In addition, both BMI (sensitivity = 0.741, specificity = 0.906) and NRI (sensitivity = 0.963, specificity = 0.601) had high sensitivity and specificity in diagnosing low muscle mass, with critical values of 19.85 and 114.177 for BMI and NRI, respectively. The oedema index was the most effective measure of body composition in detecting abnormal fluid retention with high sensitivity (92.6%) and moderate specificity (71.8%) in identifying individuals with low muscle mass. Notably, PLWH with low muscle mass participants had a significantly higher prevalence (92.6%) of a high oedema index compared with those with normal muscle mass (28.2%). This observation indicates that individuals with HIV who experience reduced muscle mass is commonly accompanied with abnormal fluid retention within the body.</p><p><strong>Conclusions: </strong>Antiretroviral medication types, specifically Zidovudine, BMI and NRI can be independent risk factors for low muscle mass in men with HIV. These factors, along with BMI, could be used conveniently to predict low muscle mass. Furthermore, the association between the oedema index and muscle mass suggests that observing signs of oedema may indicate a risk of low muscle mass in PLWH.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":null,"pages":null},"PeriodicalIF":8.9,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141625522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Myung Jin Kim, Yun Kyung Cho, Eun Hee Kim, Min Jung Lee, Woo Je Lee, Hong-Kyu Kim, Chang Hee Jung
Background: In 2023, the concept of metabolic dysfunction-associated steatotic liver disease (MASLD) was introduced as an alternative to non-alcoholic fatty liver disease (NAFLD). We aimed to assess the quantity and quality of skeletal muscle using each of these diagnostic classifications.
Methods: This cross-sectional study included 18 154 participants (11 551 [63.6%] men and 6603 [36.4%] women, mean age 53.0 ± 8.8). The participants were classified into four categories: neither steatotic liver disease (SLD), NAFLD only, MASLD only or both SLDs. An appendicular skeletal muscle mass adjusted for body mass index of <0.789 for men and <0.512 for women was defined as sarcopenia. The total abdominal muscle area (TAMA) at the L3 vertebral level was segmented into normal-attenuation muscle area (NAMA), low-attenuation muscle area and intermuscular/intramuscular adipose tissue. Myosteatosis was defined by a T-score < -1.0 of the NAMA/TAMA index, which was calculated by dividing the NAMA by the TAMA and multiplying by 100.
Results: Using subjects with neither SLD as a reference, the multivariable-adjusted odds ratios (ORs) for sarcopenia were significantly increased in those with MASLD, with adjusted ORs (95% confidence interval [CI]) of 2.62 (1.94-3.54) in the MASLD-only group and 2.33 (1.92-2.82) in the both SLDs group, while the association was insignificant in those with NAFLD only (adjusted OR [95% CI]: 2.16 [0.67-6.94]). The OR for myosteatosis was also elevated in the MASLD groups, with an OR (95% CI) of 1.75 (1.52-2.02) in subjects with MASLD only and 1.70 (1.57-1.84) in those with both SLDs, while it was slightly decreased in subjects with NAFLD only (0.52 [0.29-0.95]).
Conclusions: Employing the MASLD concept rather than that of the NAFLD proved to be more effective in distinguishing individuals with reduced muscle mass and compromised muscle quality.
{"title":"Association between metabolic dysfunction-associated steatotic liver disease and myosteatosis measured by computed tomography.","authors":"Myung Jin Kim, Yun Kyung Cho, Eun Hee Kim, Min Jung Lee, Woo Je Lee, Hong-Kyu Kim, Chang Hee Jung","doi":"10.1002/jcsm.13543","DOIUrl":"https://doi.org/10.1002/jcsm.13543","url":null,"abstract":"<p><strong>Background: </strong>In 2023, the concept of metabolic dysfunction-associated steatotic liver disease (MASLD) was introduced as an alternative to non-alcoholic fatty liver disease (NAFLD). We aimed to assess the quantity and quality of skeletal muscle using each of these diagnostic classifications.</p><p><strong>Methods: </strong>This cross-sectional study included 18 154 participants (11 551 [63.6%] men and 6603 [36.4%] women, mean age 53.0 ± 8.8). The participants were classified into four categories: neither steatotic liver disease (SLD), NAFLD only, MASLD only or both SLDs. An appendicular skeletal muscle mass adjusted for body mass index of <0.789 for men and <0.512 for women was defined as sarcopenia. The total abdominal muscle area (TAMA) at the L3 vertebral level was segmented into normal-attenuation muscle area (NAMA), low-attenuation muscle area and intermuscular/intramuscular adipose tissue. Myosteatosis was defined by a T-score < -1.0 of the NAMA/TAMA index, which was calculated by dividing the NAMA by the TAMA and multiplying by 100.</p><p><strong>Results: </strong>Using subjects with neither SLD as a reference, the multivariable-adjusted odds ratios (ORs) for sarcopenia were significantly increased in those with MASLD, with adjusted ORs (95% confidence interval [CI]) of 2.62 (1.94-3.54) in the MASLD-only group and 2.33 (1.92-2.82) in the both SLDs group, while the association was insignificant in those with NAFLD only (adjusted OR [95% CI]: 2.16 [0.67-6.94]). The OR for myosteatosis was also elevated in the MASLD groups, with an OR (95% CI) of 1.75 (1.52-2.02) in subjects with MASLD only and 1.70 (1.57-1.84) in those with both SLDs, while it was slightly decreased in subjects with NAFLD only (0.52 [0.29-0.95]).</p><p><strong>Conclusions: </strong>Employing the MASLD concept rather than that of the NAFLD proved to be more effective in distinguishing individuals with reduced muscle mass and compromised muscle quality.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":null,"pages":null},"PeriodicalIF":8.9,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141618792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Paula Aparicio, David Navarrete-Villanueva, Alba Gómez-Cabello, Tresa López-Royo, Enrique Santamaría, Joaquín Fernández-Irigoyen, Karina Ausín, Manuel Arruebo, Victor Sebastian, Germán Vicente-Rodríguez, Rosario Osta, Raquel Manzano
Background: Sarcopenia, the gradual and generalized loss of muscle mass and function with ageing, is one of the major health problems in older adults, given its high prevalence and substantial socioeconomic implications. Despite the extensive efforts to reach consensus on definition and diagnostic tests and cut-offs for sarcopenia, there is an urgent and unmet need for non-invasive, specific and sensitive biomarkers for the disease. Extracellular vesicles (EVs) are present in different biofluids including plasma, whose cargo reflects cellular physiology. This work analysed EV proteome in sarcopenia and robust patients in the search for differentially contained proteins that can be used to diagnose the disease.
Methods: Plasma small EVs (sEVs) from a total of 29 robust controls (aged 73.4 ± 5.6 years; 11 men and 18 women) and 49 sarcopenic patients (aged 82.3 ± 5.4 years; 15 men and 34 women) aged 65 years and older were isolated and their cargo was analysed by proteomics. Proteins whose concentration in sEVs was different between sarcopenic and robust patients were further validated using ELISA. The concentration of these candidates was correlated to the EWGSOP2 sarcopenia tests for low muscle strength and low physical performance, and receiver operating characteristic (ROC) curve analyses were carried out to evaluate their diagnostic power, sensitivity and specificity.
Results: Proteomic analysis identified 157 sEVs proteins in both sarcopenic and robust samples. Among them, 48 proteins had never been reported in the ExoCarta nor Vesiclepedia databases. Statistical analysis revealed eight proteins whose concentration was significantly different between groups: PF4 (log2 FC = 4.806), OIT3 (log2 FC = -1.161), MMRN1 (log2 FC = -1.982), MASP1 (log2 FC = -0.627), C1R (log2 FC = 1.830), SVEP1 (log2 FC = 1.295), VCAN (FC = 0.937) and SPTB (log2 FC = 1.243). Among them, platelet factor 4 (PF4) showed the lowest concentration while Complement C1r subcomponent (C1R) increased the most in sarcopenic patients, being these results confirmed by ELISA (P = 1.07E-09 and P = 0.001287, respectively). The concentrations of candidate proteins significantly correlated with EWGSOP2 tests currently used. ROC curve analysis showed an area under the curve of 0.8921 and 0.7476 for PF4 and C1R, respectively. Choosing the optimal for PF4, 80% sensitivity and 85.71% specificity was reached while the optimal cut-off value of C1R would allow sarcopenia diagnosis with 75% sensitivity and 66.67% specificity.
Conclusions: Our results support the determination of EV PF4 and C1R as plasma diagnostic biomarkers in sarcopenia and open the door to investigate the role of the content of these vesicles in the pathogeny of the disease.
背景:肌肉疏松症是一种随着年龄增长而逐渐和普遍出现的肌肉质量和功能丧失的疾病,是老年人的主要健康问题之一,因为其发病率高,对社会经济有重大影响。尽管人们为肌少症的定义、诊断测试和临界值达成了广泛共识,但对该疾病的非侵入性、特异性和敏感性生物标志物的需求仍十分迫切。细胞外囊泡 (EV) 存在于包括血浆在内的不同生物流体中,其载体反映了细胞的生理机能。这项研究分析了肌肉疏松症和健壮患者体内的EV蛋白质组,以寻找可用于诊断该疾病的不同蛋白质:方法:分离了29名壮年对照组患者(年龄为73.4 ± 5.6岁,男性11人,女性18人)和49名65岁及以上的肌肉疏松症患者(年龄为82.3 ± 5.4岁,男性15人,女性34人)的血浆小EVs(sEVs),并通过蛋白质组学分析了它们的载体。使用 ELISA 方法进一步验证了肌肉疏松患者和健壮患者 sEV 中浓度不同的蛋白质。这些候选蛋白的浓度与 EWGSOP2 肌肉疏松症测试(低肌力和低体能)相关,并进行了接收器操作特征曲线(ROC)分析,以评估其诊断能力、灵敏度和特异性:蛋白质组分析在肌少症和健壮样本中发现了 157 个 sEVs 蛋白质。其中有 48 个蛋白质从未在 ExoCarta 或 Vesiclepedia 数据库中出现过。统计分析显示,有 8 种蛋白质的浓度在不同组间存在显著差异:PF4(log2 FC = 4.806)、OIT3(log2 FC =-1.161)、MMRN1(log2 FC =-1.982)、MASP1(log2 FC =-0.627)、C1R(log2 FC = 1.830)、SVEP1(log2 FC = 1.295)、VCAN(FC = 0.937)和SPTB(log2 FC = 1.243)。其中,血小板因子 4(PF4)的浓度最低,而补体 C1r 亚组分(C1R)在肌无力患者中的浓度增加最多,ELISA 证实了这些结果(P = 1.07E-09 和 P = 0.001287)。候选蛋白质的浓度与目前使用的 EWGSOP2 检测方法有明显的相关性。ROC 曲线分析显示,PF4 和 C1R 的曲线下面积分别为 0.8921 和 0.7476。选择 PF4 的最佳值,灵敏度为 80%,特异性为 85.71%,而选择 C1R 的最佳截断值,则可诊断肌肉疏松症,灵敏度为 75%,特异性为 66.67%:我们的研究结果支持将 EV PF4 和 C1R 确定为肌肉疏松症的血浆诊断生物标志物,并为研究这些囊泡内容物在疾病病因中的作用打开了大门。
{"title":"Proteomic profiling of human plasma extracellular vesicles identifies PF4 and C1R as novel biomarker in sarcopenia.","authors":"Paula Aparicio, David Navarrete-Villanueva, Alba Gómez-Cabello, Tresa López-Royo, Enrique Santamaría, Joaquín Fernández-Irigoyen, Karina Ausín, Manuel Arruebo, Victor Sebastian, Germán Vicente-Rodríguez, Rosario Osta, Raquel Manzano","doi":"10.1002/jcsm.13539","DOIUrl":"https://doi.org/10.1002/jcsm.13539","url":null,"abstract":"<p><strong>Background: </strong>Sarcopenia, the gradual and generalized loss of muscle mass and function with ageing, is one of the major health problems in older adults, given its high prevalence and substantial socioeconomic implications. Despite the extensive efforts to reach consensus on definition and diagnostic tests and cut-offs for sarcopenia, there is an urgent and unmet need for non-invasive, specific and sensitive biomarkers for the disease. Extracellular vesicles (EVs) are present in different biofluids including plasma, whose cargo reflects cellular physiology. This work analysed EV proteome in sarcopenia and robust patients in the search for differentially contained proteins that can be used to diagnose the disease.</p><p><strong>Methods: </strong>Plasma small EVs (sEVs) from a total of 29 robust controls (aged 73.4 ± 5.6 years; 11 men and 18 women) and 49 sarcopenic patients (aged 82.3 ± 5.4 years; 15 men and 34 women) aged 65 years and older were isolated and their cargo was analysed by proteomics. Proteins whose concentration in sEVs was different between sarcopenic and robust patients were further validated using ELISA. The concentration of these candidates was correlated to the EWGSOP2 sarcopenia tests for low muscle strength and low physical performance, and receiver operating characteristic (ROC) curve analyses were carried out to evaluate their diagnostic power, sensitivity and specificity.</p><p><strong>Results: </strong>Proteomic analysis identified 157 sEVs proteins in both sarcopenic and robust samples. Among them, 48 proteins had never been reported in the ExoCarta nor Vesiclepedia databases. Statistical analysis revealed eight proteins whose concentration was significantly different between groups: PF4 (log2 FC = 4.806), OIT3 (log2 FC = -1.161), MMRN1 (log2 FC = -1.982), MASP1 (log2 FC = -0.627), C1R (log2 FC = 1.830), SVEP1 (log2 FC = 1.295), VCAN (FC = 0.937) and SPTB (log2 FC = 1.243). Among them, platelet factor 4 (PF4) showed the lowest concentration while Complement C1r subcomponent (C1R) increased the most in sarcopenic patients, being these results confirmed by ELISA (P = 1.07E-09 and P = 0.001287, respectively). The concentrations of candidate proteins significantly correlated with EWGSOP2 tests currently used. ROC curve analysis showed an area under the curve of 0.8921 and 0.7476 for PF4 and C1R, respectively. Choosing the optimal for PF4, 80% sensitivity and 85.71% specificity was reached while the optimal cut-off value of C1R would allow sarcopenia diagnosis with 75% sensitivity and 66.67% specificity.</p><p><strong>Conclusions: </strong>Our results support the determination of EV PF4 and C1R as plasma diagnostic biomarkers in sarcopenia and open the door to investigate the role of the content of these vesicles in the pathogeny of the disease.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":null,"pages":null},"PeriodicalIF":8.9,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141618794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Andrew M Holwerda, Marlou L Dirks, Pierre-Andre Barbeau, Joy Goessens, Annemie Gijsen, Luc J C van Loon, Graham P Holloway
Background: Mitochondria represent key organelles influencing cellular homeostasis and have been implicated in the signalling events regulating protein synthesis.
Methods: We examined whether mitochondrial bioenergetics (oxidative phosphorylation and reactive oxygen species (H2O2) emission, ROS) measured in vitro in permeabilized muscle fibres represent regulatory factors for integrated daily muscle protein synthesis rates and skeletal muscle mass changes across the spectrum of physical activity, including free-living and bed-rest conditions: n = 19 healthy, young men (26 ± 4 years, 23.4 ± 3.3 kg/m2) and following 12 weeks of resistance-type exercise training: n = 10 healthy older men (70 ± 3 years, 25.2 ± 2.1 kg/m2). Additionally, we evaluated the direct relationship between attenuated mitochondrial ROS emission and integrated daily myofibrillar and sarcoplasmic protein synthesis rates in genetically modified mice (mitochondrial-targeted catalase, MCAT).
Results: Neither oxidative phosphorylation nor H2O2 emission were associated with muscle protein synthesis rates in healthy young men under free-living conditions or following 1 week of bed rest (both P > 0.05). Greater increases in GSSG concentration were associated with greater skeletal muscle mass loss following bed rest (r = -0.49, P < 0.05). In older men, only submaximal mitochondrial oxidative phosphorylation (corrected for mitochondrial content) was positively associated with myofibrillar protein synthesis rates during exercise training (r = 0.72, P < 0.05). However, changes in oxidative phosphorylation and H2O2 emission were not associated with changes in skeletal muscle mass following training (both P > 0.05). Additionally, MCAT mice displayed no differences in myofibrillar (2.62 ± 0.22 vs. 2.75 ± 0.15%/day) and sarcoplasmic (3.68 ± 0.35 vs. 3.54 ± 0.35%/day) protein synthesis rates when compared with wild-type mice (both P > 0.05).
Conclusions: Mitochondrial oxidative phosphorylation and reactive oxygen emission do not seem to represent key factors regulating muscle protein synthesis or muscle mass regulation across the spectrum of physical activity.
{"title":"Mitochondrial bioenergetics are not associated with myofibrillar protein synthesis rates.","authors":"Andrew M Holwerda, Marlou L Dirks, Pierre-Andre Barbeau, Joy Goessens, Annemie Gijsen, Luc J C van Loon, Graham P Holloway","doi":"10.1002/jcsm.13532","DOIUrl":"https://doi.org/10.1002/jcsm.13532","url":null,"abstract":"<p><strong>Background: </strong>Mitochondria represent key organelles influencing cellular homeostasis and have been implicated in the signalling events regulating protein synthesis.</p><p><strong>Methods: </strong>We examined whether mitochondrial bioenergetics (oxidative phosphorylation and reactive oxygen species (H<sub>2</sub>O<sub>2</sub>) emission, ROS) measured in vitro in permeabilized muscle fibres represent regulatory factors for integrated daily muscle protein synthesis rates and skeletal muscle mass changes across the spectrum of physical activity, including free-living and bed-rest conditions: n = 19 healthy, young men (26 ± 4 years, 23.4 ± 3.3 kg/m<sup>2</sup>) and following 12 weeks of resistance-type exercise training: n = 10 healthy older men (70 ± 3 years, 25.2 ± 2.1 kg/m<sup>2</sup>). Additionally, we evaluated the direct relationship between attenuated mitochondrial ROS emission and integrated daily myofibrillar and sarcoplasmic protein synthesis rates in genetically modified mice (mitochondrial-targeted catalase, MCAT).</p><p><strong>Results: </strong>Neither oxidative phosphorylation nor H<sub>2</sub>O<sub>2</sub> emission were associated with muscle protein synthesis rates in healthy young men under free-living conditions or following 1 week of bed rest (both P > 0.05). Greater increases in GSSG concentration were associated with greater skeletal muscle mass loss following bed rest (r = -0.49, P < 0.05). In older men, only submaximal mitochondrial oxidative phosphorylation (corrected for mitochondrial content) was positively associated with myofibrillar protein synthesis rates during exercise training (r = 0.72, P < 0.05). However, changes in oxidative phosphorylation and H<sub>2</sub>O<sub>2</sub> emission were not associated with changes in skeletal muscle mass following training (both P > 0.05). Additionally, MCAT mice displayed no differences in myofibrillar (2.62 ± 0.22 vs. 2.75 ± 0.15%/day) and sarcoplasmic (3.68 ± 0.35 vs. 3.54 ± 0.35%/day) protein synthesis rates when compared with wild-type mice (both P > 0.05).</p><p><strong>Conclusions: </strong>Mitochondrial oxidative phosphorylation and reactive oxygen emission do not seem to represent key factors regulating muscle protein synthesis or muscle mass regulation across the spectrum of physical activity.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":null,"pages":null},"PeriodicalIF":8.9,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141615418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Matthias Jung, Hanna Rieder, Marco Reisert, Susanne Rospleszcz, Johanna Nattenmueller, Annette Peters, Christopher L Schlett, Fabian Bamberg, Jakob Weiss
Background: There is increasing evidence that myosteatosis, which is currently not assessed in clinical routine, plays an important role in risk estimation in individuals with impaired glucose metabolism, as it is associated with the progression of insulin resistance. With advances in artificial intelligence, automated and accurate algorithms have become feasible to fill this gap.
Methods: In this retrospective study, we developed and tested a fully automated deep learning model using data from two prospective cohort studies (German National Cohort [NAKO] and Cooperative Health Research in the Region of Augsburg [KORA]) to quantify myosteatosis on whole-body T1-weighted Dixon magnetic resonance imaging as (1) intramuscular adipose tissue (IMAT; the current standard) and (2) quantitative skeletal muscle (SM) fat fraction (SMFF). Subsequently, we investigated the two measures for their discrimination of and association with impaired glucose metabolism beyond baseline demographics (age, sex and body mass index [BMI]) and cardiometabolic risk factors (lipid panel, systolic blood pressure, smoking status and alcohol consumption) in asymptomatic individuals from the KORA study. Impaired glucose metabolism was defined as impaired fasting glucose or impaired glucose tolerance (140-200 mg/dL) or prevalent diabetes mellitus.
Results: Model performance was high, with Dice coefficients of ≥0.81 for IMAT and ≥0.91 for SM in the internal (NAKO) and external (KORA) testing sets. In the target population (380 KORA participants: mean age of 53.6 ± 9.2 years, BMI of 28.2 ± 4.9 kg/m2, 57.4% male), individuals with impaired glucose metabolism (n = 146; 38.4%) were older and more likely men and showed a higher cardiometabolic risk profile, higher IMAT (4.5 ± 2.2% vs. 3.9 ± 1.7%) and higher SMFF (22.0 ± 4.7% vs. 18.9 ± 3.9%) compared to normoglycaemic controls (all P ≤ 0.005). SMFF showed better discrimination for impaired glucose metabolism than IMAT (area under the receiver operating characteristic curve [AUC] 0.693 vs. 0.582, 95% confidence interval [CI] [0.06-0.16]; P < 0.001) but was not significantly different from BMI (AUC 0.733 vs. 0.693, 95% CI [-0.09 to 0.01]; P = 0.15). In univariable logistic regression, IMAT (odds ratio [OR] = 1.18, 95% CI [1.06-1.32]; P = 0.004) and SMFF (OR = 1.19, 95% CI [1.13-1.26]; P < 0.001) were associated with a higher risk of impaired glucose metabolism. This signal remained robust after multivariable adjustment for baseline demographics and cardiometabolic risk factors for SMFF (OR = 1.10, 95% CI [1.01-1.19]; P = 0.028) but not for IMAT (OR = 1.14, 95% CI [0.97-1.33]; P = 0.11).
Conclusions: Quantitative SMFF, but not IMAT, is an independent predictor of impaired glucose metabolism, and discrimination is not significantly different from BMI, making it a promising alternative for the currently established approach. Automated method
背景:越来越多的证据表明,目前在临床常规中尚未评估的骨质疏松症在糖代谢受损患者的风险评估中起着重要作用,因为它与胰岛素抵抗的进展有关。随着人工智能技术的进步,自动化的精确算法已经可以填补这一空白:在这项回顾性研究中,我们利用两项前瞻性队列研究(德国国家队列[NAKO]和奥格斯堡地区合作健康研究[KORA])的数据,开发并测试了一个全自动深度学习模型,将全身 T1 加权迪克森磁共振成像上的肌骨肥大症量化为(1)肌肉内脂肪组织(IMAT;现行标准)和(2)定量骨骼肌(SM)脂肪分数(SMFF)。随后,我们在 KORA 研究的无症状个体中研究了这两种测量方法对葡萄糖代谢受损的辨别力以及与之的关联,而不局限于基线人口统计学指标(年龄、性别和体重指数 [BMI])和心血管代谢风险因素(血脂组合、收缩压、吸烟状况和饮酒量)。糖代谢受损被定义为空腹血糖受损或糖耐量受损(140-200 毫克/分升)或流行性糖尿病:模型性能很高,在内部(NAKO)和外部(KORA)测试集中,IMAT的Dice系数≥0.81,SM的Dice系数≥0.91。在目标人群(380 名 KORA 参与者:平均年龄为 53.6 ± 9.2 岁,体重指数为 28.2 ± 4.9 kg/m2,57.4% 为男性)中,糖代谢受损者(n = 146;38.与正常血糖对照组相比,糖代谢受损者(n = 146;38.4%)年龄更大,更可能是男性,并显示出更高的心脏代谢风险特征、更高的 IMAT(4.5 ± 2.2% vs. 3.9 ± 1.7%)和更高的 SMFF(22.0 ± 4.7% vs. 18.9 ± 3.9%)(所有 P 均≤0.005)。与 IMAT 相比,SMFF 对糖代谢受损的判别能力更强(接收器操作特征曲线下面积 [AUC] 0.693 vs. 0.582,95% 置信区间 [CI] [0.06-0.16];P 结论:SMFF 比 IMAT 更能判别糖代谢受损:定量 SMFF(而非 IMAT)是糖代谢受损的独立预测指标,且与 BMI 的区分度无显著差异,使其有望替代现有方法。自动方法(如所提出的模型)可为肌骨质疏松症的机会性筛查提供一种可行的选择,从而提供一种低成本的个性化风险评估解决方案。
{"title":"Association between myosteatosis and impaired glucose metabolism: A deep learning whole-body magnetic resonance imaging population phenotyping approach.","authors":"Matthias Jung, Hanna Rieder, Marco Reisert, Susanne Rospleszcz, Johanna Nattenmueller, Annette Peters, Christopher L Schlett, Fabian Bamberg, Jakob Weiss","doi":"10.1002/jcsm.13527","DOIUrl":"https://doi.org/10.1002/jcsm.13527","url":null,"abstract":"<p><strong>Background: </strong>There is increasing evidence that myosteatosis, which is currently not assessed in clinical routine, plays an important role in risk estimation in individuals with impaired glucose metabolism, as it is associated with the progression of insulin resistance. With advances in artificial intelligence, automated and accurate algorithms have become feasible to fill this gap.</p><p><strong>Methods: </strong>In this retrospective study, we developed and tested a fully automated deep learning model using data from two prospective cohort studies (German National Cohort [NAKO] and Cooperative Health Research in the Region of Augsburg [KORA]) to quantify myosteatosis on whole-body T1-weighted Dixon magnetic resonance imaging as (1) intramuscular adipose tissue (IMAT; the current standard) and (2) quantitative skeletal muscle (SM) fat fraction (SMFF). Subsequently, we investigated the two measures for their discrimination of and association with impaired glucose metabolism beyond baseline demographics (age, sex and body mass index [BMI]) and cardiometabolic risk factors (lipid panel, systolic blood pressure, smoking status and alcohol consumption) in asymptomatic individuals from the KORA study. Impaired glucose metabolism was defined as impaired fasting glucose or impaired glucose tolerance (140-200 mg/dL) or prevalent diabetes mellitus.</p><p><strong>Results: </strong>Model performance was high, with Dice coefficients of ≥0.81 for IMAT and ≥0.91 for SM in the internal (NAKO) and external (KORA) testing sets. In the target population (380 KORA participants: mean age of 53.6 ± 9.2 years, BMI of 28.2 ± 4.9 kg/m<sup>2</sup>, 57.4% male), individuals with impaired glucose metabolism (n = 146; 38.4%) were older and more likely men and showed a higher cardiometabolic risk profile, higher IMAT (4.5 ± 2.2% vs. 3.9 ± 1.7%) and higher SMFF (22.0 ± 4.7% vs. 18.9 ± 3.9%) compared to normoglycaemic controls (all P ≤ 0.005). SMFF showed better discrimination for impaired glucose metabolism than IMAT (area under the receiver operating characteristic curve [AUC] 0.693 vs. 0.582, 95% confidence interval [CI] [0.06-0.16]; P < 0.001) but was not significantly different from BMI (AUC 0.733 vs. 0.693, 95% CI [-0.09 to 0.01]; P = 0.15). In univariable logistic regression, IMAT (odds ratio [OR] = 1.18, 95% CI [1.06-1.32]; P = 0.004) and SMFF (OR = 1.19, 95% CI [1.13-1.26]; P < 0.001) were associated with a higher risk of impaired glucose metabolism. This signal remained robust after multivariable adjustment for baseline demographics and cardiometabolic risk factors for SMFF (OR = 1.10, 95% CI [1.01-1.19]; P = 0.028) but not for IMAT (OR = 1.14, 95% CI [0.97-1.33]; P = 0.11).</p><p><strong>Conclusions: </strong>Quantitative SMFF, but not IMAT, is an independent predictor of impaired glucose metabolism, and discrimination is not significantly different from BMI, making it a promising alternative for the currently established approach. Automated method","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":null,"pages":null},"PeriodicalIF":8.9,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141618793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}