Georgia Lenihan-Geels, Francisco Garcia Carrizo, Marina Leer, Sabrina Gohlke, Moritz Oster, Sophie Pöhle-Kronawitter, Christiane Ott, Alexandra Chadt, Isabel N Reinisch, Markus Galhuber, Chen Li, Wenke Jonas, Markus Jähnert, Susanne Klaus, Hadi Al-Hasani, Tilman Grune, Annette Schürmann, Tobias Madl, Andreas Prokesch, Michael Schupp, Tim J Schulz
Background: The ability of skeletal muscle to respond adequately to changes in nutrient availability, known as metabolic flexibility, is essential for the maintenance of metabolic health and loss of flexibility contributes to the development of diabetes and obesity. The tumour suppressor protein, p53, has been linked to the control of energy metabolism. We assessed its role in the acute control of nutrient allocation in skeletal muscle in the context of limited nutrient availability.
Methods: A mouse model with inducible deletion of the p53-encoding gene, Trp53, in skeletal muscle was generated using the Cre-loxP-system. A detailed analysis of nutrient metabolism in mice with control and knockout genotypes was performed under ad libitum fed and fasting conditions and in exercised mice.
Results: Acute deletion of p53 in myofibres of mice activated catabolic nutrient usage pathways even under ad libitum fed conditions, resulting in significantly increased overall energy expenditure (+10.6%; P = 0.0385) and a severe nutrient deficit in muscle characterized by depleted intramuscular glucose and glycogen levels (-62,0%; P < 0.0001 and -52.7%; P < 0.0001, respectively). This was accompanied by changes in marker gene expression patterns of circadian rhythmicity and hyperactivity (+57.4%; P = 0.0068). These metabolic changes occurred acutely, within 2-3 days after deletion of Trp53 was initiated, suggesting a rapid adaptive response to loss of p53, which resulted in a transient increase in lactate release to the circulation (+46.6%; P = 0.0115) from non-exercised muscle as a result of elevated carbohydrate mobilization. Conversely, an impairment of proteostasis and amino acid metabolism was observed in knockout mice during fasting. During endurance exercise testing, mice with acute, muscle-specific Trp53 inactivation displayed an early exhaustion phenotype with a premature shift in fuel usage and reductions in multiple performance parameters, including a significantly reduced running time and distance (-13.8%; P = 0.049 and -22.2%; P = 0.0384, respectively).
Conclusions: These findings suggest that efficient nutrient conservation is a key element of normal metabolic homeostasis that is sustained by p53. The homeostatic state in metabolic tissues is actively maintained to coordinate efficient energy conservation and metabolic flexibility towards nutrient stress. The acute deletion of Trp53 unlocks mechanisms that suppress the activity of nutrient catabolic pathways, causing substantial loss of intramuscular energy stores, which contributes to a fasting-like state in muscle tissue. Altogether, these findings uncover a novel function of p53 in the short-term regulation of nutrient metabolism in skeletal muscle and show that p53 serves to maintain metabolic homeostasis and efficient energy conservation.
{"title":"Skeletal muscle p53-depletion uncovers a mechanism of fuel usage suppression that enables efficient energy conservation.","authors":"Georgia Lenihan-Geels, Francisco Garcia Carrizo, Marina Leer, Sabrina Gohlke, Moritz Oster, Sophie Pöhle-Kronawitter, Christiane Ott, Alexandra Chadt, Isabel N Reinisch, Markus Galhuber, Chen Li, Wenke Jonas, Markus Jähnert, Susanne Klaus, Hadi Al-Hasani, Tilman Grune, Annette Schürmann, Tobias Madl, Andreas Prokesch, Michael Schupp, Tim J Schulz","doi":"10.1002/jcsm.13529","DOIUrl":"https://doi.org/10.1002/jcsm.13529","url":null,"abstract":"<p><strong>Background: </strong>The ability of skeletal muscle to respond adequately to changes in nutrient availability, known as metabolic flexibility, is essential for the maintenance of metabolic health and loss of flexibility contributes to the development of diabetes and obesity. The tumour suppressor protein, p53, has been linked to the control of energy metabolism. We assessed its role in the acute control of nutrient allocation in skeletal muscle in the context of limited nutrient availability.</p><p><strong>Methods: </strong>A mouse model with inducible deletion of the p53-encoding gene, Trp53, in skeletal muscle was generated using the Cre-loxP-system. A detailed analysis of nutrient metabolism in mice with control and knockout genotypes was performed under ad libitum fed and fasting conditions and in exercised mice.</p><p><strong>Results: </strong>Acute deletion of p53 in myofibres of mice activated catabolic nutrient usage pathways even under ad libitum fed conditions, resulting in significantly increased overall energy expenditure (+10.6%; P = 0.0385) and a severe nutrient deficit in muscle characterized by depleted intramuscular glucose and glycogen levels (-62,0%; P < 0.0001 and -52.7%; P < 0.0001, respectively). This was accompanied by changes in marker gene expression patterns of circadian rhythmicity and hyperactivity (+57.4%; P = 0.0068). These metabolic changes occurred acutely, within 2-3 days after deletion of Trp53 was initiated, suggesting a rapid adaptive response to loss of p53, which resulted in a transient increase in lactate release to the circulation (+46.6%; P = 0.0115) from non-exercised muscle as a result of elevated carbohydrate mobilization. Conversely, an impairment of proteostasis and amino acid metabolism was observed in knockout mice during fasting. During endurance exercise testing, mice with acute, muscle-specific Trp53 inactivation displayed an early exhaustion phenotype with a premature shift in fuel usage and reductions in multiple performance parameters, including a significantly reduced running time and distance (-13.8%; P = 0.049 and -22.2%; P = 0.0384, respectively).</p><p><strong>Conclusions: </strong>These findings suggest that efficient nutrient conservation is a key element of normal metabolic homeostasis that is sustained by p53. The homeostatic state in metabolic tissues is actively maintained to coordinate efficient energy conservation and metabolic flexibility towards nutrient stress. The acute deletion of Trp53 unlocks mechanisms that suppress the activity of nutrient catabolic pathways, causing substantial loss of intramuscular energy stores, which contributes to a fasting-like state in muscle tissue. Altogether, these findings uncover a novel function of p53 in the short-term regulation of nutrient metabolism in skeletal muscle and show that p53 serves to maintain metabolic homeostasis and efficient energy conservation.</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":"141618795","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}
Overeating and inactivity are associated with type 2 diabetes. This study aimed to investigate its pathological basis using integrated omics and db/db/mice, a model representing this condition.
{"title":"A multi-omics approach to overeating and inactivity-induced muscle atrophy in db/db mice","authors":"Takuro Okamura, Masahide Hamaguchi, Genki Kobayashi, Takahiro Ichikawa, Yuka Hasegawa, Tomoki Miyoshi, Takafumi Senmaru, Naoko Nakanishi, Ryoichi Sasano, Michiaki Fukui","doi":"10.1002/jcsm.13550","DOIUrl":"https://doi.org/10.1002/jcsm.13550","url":null,"abstract":"Overeating and inactivity are associated with type 2 diabetes. This study aimed to investigate its pathological basis using integrated omics and <i>db/db/m</i>ice, a model representing this condition.","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":null,"pages":null},"PeriodicalIF":8.9,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141602820","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}
Samet Agca, Aylin Domaniku-Waraich, Sevval Nur Bilgic, Melis Sucuoglu, Meric Dag, Sukru Anil Dogan, Serkan Kir
Background: Tumour-induced skeletal muscle wasting in the context of cancer cachexia is a condition with profound implications for patient survival. The loss of muscle mass is a significant clinical obstacle and is linked to reduced tolerance to chemotherapy and increased frailty. Understanding the molecular mechanisms driving muscle atrophy is crucial for the design of new therapeutics.
Methods: Lewis lung carcinoma tumours were utilized to induce cachexia and muscle atrophy in mice. Single-nucleus libraries of the tibialis anterior (TA) muscle from tumour-bearing mice and their non-tumour-bearing controls were constructed using 10X Genomics applications following the manufacturer's guidelines. RNA sequencing results were analysed with Cell Ranger software and the Seurat R package. Oxygen consumption of mitochondria isolated from TA muscle was measured using an Oroboros O2k-FluoRespirometer. Mouse primary myotubes were treated with a recombinant ectodysplasin A2 (EDA-A2) protein to activate EDA-A2 receptor (EDA2R) signalling and study changes in gene expression and oxygen consumption.
Results: Tumour-bearing mice were sacrificed while exhibiting moderate cachexia. Average TA muscle weight was reduced by 11% (P = 0.0207) in these mice. A total of 12 335 nuclei, comprising 6422 nuclei from the control group and 5892 nuclei from atrophying muscles, were studied. The analysis of single-nucleus transcriptomes identified distinct myonuclear gene signatures and a shift towards type IIb myonuclei. Muscle atrophy-related genes, including Atrogin1, MuRF1 and Eda2r, were upregulated in these myonuclei, emphasizing their crucial roles in muscle wasting. Gene set enrichment analysis demonstrated that EDA2R activation and tumour inoculation led to similar expression patterns in muscle cells, including the stimulation of nuclear factor-kappa B, Janus kinase-signal transducer and activator of transcription and transforming growth factor-beta pathways and the suppression of myogenesis and oxidative phosphorylation. Muscle oxidative metabolism was suppressed by both tumours and EDA2R activation.
Conclusions: This study identified tumour-induced transcriptional changes in muscle tissue at single-nucleus resolution and highlighted the negative impact of tumours on oxidative metabolism. These findings contribute to a deeper understanding of the molecular mechanisms underlying muscle wasting.
{"title":"Tumour-induced alterations in single-nucleus transcriptome of atrophying muscles indicate enhanced protein degradation and reduced oxidative metabolism.","authors":"Samet Agca, Aylin Domaniku-Waraich, Sevval Nur Bilgic, Melis Sucuoglu, Meric Dag, Sukru Anil Dogan, Serkan Kir","doi":"10.1002/jcsm.13540","DOIUrl":"https://doi.org/10.1002/jcsm.13540","url":null,"abstract":"<p><strong>Background: </strong>Tumour-induced skeletal muscle wasting in the context of cancer cachexia is a condition with profound implications for patient survival. The loss of muscle mass is a significant clinical obstacle and is linked to reduced tolerance to chemotherapy and increased frailty. Understanding the molecular mechanisms driving muscle atrophy is crucial for the design of new therapeutics.</p><p><strong>Methods: </strong>Lewis lung carcinoma tumours were utilized to induce cachexia and muscle atrophy in mice. Single-nucleus libraries of the tibialis anterior (TA) muscle from tumour-bearing mice and their non-tumour-bearing controls were constructed using 10X Genomics applications following the manufacturer's guidelines. RNA sequencing results were analysed with Cell Ranger software and the Seurat R package. Oxygen consumption of mitochondria isolated from TA muscle was measured using an Oroboros O2k-FluoRespirometer. Mouse primary myotubes were treated with a recombinant ectodysplasin A2 (EDA-A2) protein to activate EDA-A2 receptor (EDA2R) signalling and study changes in gene expression and oxygen consumption.</p><p><strong>Results: </strong>Tumour-bearing mice were sacrificed while exhibiting moderate cachexia. Average TA muscle weight was reduced by 11% (P = 0.0207) in these mice. A total of 12 335 nuclei, comprising 6422 nuclei from the control group and 5892 nuclei from atrophying muscles, were studied. The analysis of single-nucleus transcriptomes identified distinct myonuclear gene signatures and a shift towards type IIb myonuclei. Muscle atrophy-related genes, including Atrogin1, MuRF1 and Eda2r, were upregulated in these myonuclei, emphasizing their crucial roles in muscle wasting. Gene set enrichment analysis demonstrated that EDA2R activation and tumour inoculation led to similar expression patterns in muscle cells, including the stimulation of nuclear factor-kappa B, Janus kinase-signal transducer and activator of transcription and transforming growth factor-beta pathways and the suppression of myogenesis and oxidative phosphorylation. Muscle oxidative metabolism was suppressed by both tumours and EDA2R activation.</p><p><strong>Conclusions: </strong>This study identified tumour-induced transcriptional changes in muscle tissue at single-nucleus resolution and highlighted the negative impact of tumours on oxidative metabolism. These findings contribute to a deeper understanding of the molecular mechanisms underlying muscle wasting.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":null,"pages":null},"PeriodicalIF":8.9,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141597978","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}
Javier Hurtado-Oliva, Aniek T Zwart, Jeroen Vister, Anouk van der Hoorn, Roel J H M Steenbakkers, Inge Wegner, Gyorgy B Halmos
Background: Measuring the swallowing muscle mass with volume measurements is complex and time intensive; therefore, it is not used in clinical practice. However, it can be clinically relevant, for instance, in the case of sarcopenic dysphagia. The aim of the study was to develop a feasible and clinically applicable method to measure swallowing muscle mass.
Methods: Data from 10 head and neck cancer patients were collected from the Oncological Life Study data-biobank of the University Medical Center Groningen. The pharyngeal constrictor, genioglossus, mylohyoid and geniohyoid complex muscles, as well as the tongue complex muscles, were delineated manually on routinely performed head and neck computed tomography scans. Axial and sagittal planes were used for volume and area measurements, respectively. Muscle density measurements were performed with and without Hounsfield unit thresholding. Correlations were assessed by Pearson correlation coefficients, and interobserver reliability was measured using intra-class correlation coefficients (ICCs).
Results: Significant differences were observed between sagittal area measurements with and without Hounsfield unit thresholds for pharyngeal constrictor, tongue complex and the sum of the swallowing muscles (t > 6; P-value < 0.001). Stronger correlations emerged without Hounsfield unit thresholding. Strong positive and significant correlations were found between the total swallowing muscle mass volume and the sagittal area of the tongue complex muscles (r = 0.87, P-value < 0.05) and the sum of the sagittal areas of the pharyngeal constrictor and tongue complex muscles (r = 0.85, P-value < 0.05). The use of the Hounsfield unit threshold weakened correlations. Interobserver reliability was assessed and found to be fair to good for the pharyngeal constrictor muscle (ICC = 0.68, P-value < 0.05), excellent for the tongue complex muscles (ICC = 0.98, P-value < 0.05) and excellent for the total swallowing muscle area (ICC = 0.96, P-value < 0.05).
Conclusions: Single-slice delineation of the sagittal area of tongue complex muscle and pharyngeal constrictor muscle is a promising, fast, simple and clinically applicable method for measuring the total volume of the swallowing muscle mass in head and neck cancer patients without Hounsfield unit thresholding. These advancements and findings would help in the early and accurate diagnosis of definitive sarcopenic dysphagia.
{"title":"A new computed tomography-based approach to quantify swallowing muscle volume by measuring tongue muscle area in a single slice.","authors":"Javier Hurtado-Oliva, Aniek T Zwart, Jeroen Vister, Anouk van der Hoorn, Roel J H M Steenbakkers, Inge Wegner, Gyorgy B Halmos","doi":"10.1002/jcsm.13537","DOIUrl":"https://doi.org/10.1002/jcsm.13537","url":null,"abstract":"<p><strong>Background: </strong>Measuring the swallowing muscle mass with volume measurements is complex and time intensive; therefore, it is not used in clinical practice. However, it can be clinically relevant, for instance, in the case of sarcopenic dysphagia. The aim of the study was to develop a feasible and clinically applicable method to measure swallowing muscle mass.</p><p><strong>Methods: </strong>Data from 10 head and neck cancer patients were collected from the Oncological Life Study data-biobank of the University Medical Center Groningen. The pharyngeal constrictor, genioglossus, mylohyoid and geniohyoid complex muscles, as well as the tongue complex muscles, were delineated manually on routinely performed head and neck computed tomography scans. Axial and sagittal planes were used for volume and area measurements, respectively. Muscle density measurements were performed with and without Hounsfield unit thresholding. Correlations were assessed by Pearson correlation coefficients, and interobserver reliability was measured using intra-class correlation coefficients (ICCs).</p><p><strong>Results: </strong>Significant differences were observed between sagittal area measurements with and without Hounsfield unit thresholds for pharyngeal constrictor, tongue complex and the sum of the swallowing muscles (t > 6; P-value < 0.001). Stronger correlations emerged without Hounsfield unit thresholding. Strong positive and significant correlations were found between the total swallowing muscle mass volume and the sagittal area of the tongue complex muscles (r = 0.87, P-value < 0.05) and the sum of the sagittal areas of the pharyngeal constrictor and tongue complex muscles (r = 0.85, P-value < 0.05). The use of the Hounsfield unit threshold weakened correlations. Interobserver reliability was assessed and found to be fair to good for the pharyngeal constrictor muscle (ICC = 0.68, P-value < 0.05), excellent for the tongue complex muscles (ICC = 0.98, P-value < 0.05) and excellent for the total swallowing muscle area (ICC = 0.96, P-value < 0.05).</p><p><strong>Conclusions: </strong>Single-slice delineation of the sagittal area of tongue complex muscle and pharyngeal constrictor muscle is a promising, fast, simple and clinically applicable method for measuring the total volume of the swallowing muscle mass in head and neck cancer patients without Hounsfield unit thresholding. These advancements and findings would help in the early and accurate diagnosis of definitive sarcopenic dysphagia.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":null,"pages":null},"PeriodicalIF":8.9,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141597975","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}
Jie Guo, Yuxia Wei, Emerald G Heiland, Anna Marseglia
Background: The distribution of fat and muscle mass in different regions of the body can reflect different pathways to mortality in individuals with diabetes. Therefore, we investigated the associations between whole-body and regional body fat and muscle mass with cardiovascular disease (CVD) and non-CVD mortality in type 2 diabetes (T2D).
Methods: Within the National Health and Nutrition Examination Survey 1999-2006, 1417 adults aged ≥50 years with T2D were selected. Dual-energy X-ray absorptiometry was used to derive whole-body, trunk, arm, and leg fat mass and muscle mass indices (FMI and MMI). Mortality data until 31 December 2019 were retrieved from the National Death Index. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated from Cox proportional hazard models.
Results: A total of 1417 participants were included in this study (weighted mean age [standard error]: 63.7 [0.3] years; 50.5% female). Over a median follow-up of 13.6 years, 797 deaths were recorded (371 CVD-related and 426 non-CVD deaths). Higher FMI in the arm was associated with increased risk of non-CVD mortality (fourth quartile [Q4] vs. first quartile [Q1]: HR 1.82 [95% CI 1.13-2.94]), whereas higher FMI in the trunk or leg was not significantly associated with CVD or non-CVD mortality. Conversely, higher arm MMI was associated with a lower risk of both CVD (Q4 vs. Q1: HR 0.51 [95% CI 0.33-0.81]) and non-CVD (Q4 vs. Q1: HR 0.56 [95% CI 0.33-0.94]) mortality. There was a significant interaction between smoking status and arm FMI on non-CVD mortality (P for interaction = 0.007). Higher arm FMI was associated with a higher risk of non-CVD mortality among current or former smokers (Q4 vs. Q1: HR 2.67 [95% CI 1.46-4.88]) but not non-smokers (Q4 vs. Q1: HR 0.85 [95% CI 0.49-1.47]).
Conclusions: Fat mass and muscle mass, especially in the arm, are differently associated with CVD and non-CVD mortality in people with T2D. Our findings underscore the predictive value of body compositions in the arm in forecasting mortality among older adults with T2D.
背景:脂肪和肌肉质量在身体不同区域的分布可反映糖尿病患者死亡的不同途径。因此,我们研究了2型糖尿病(T2D)患者全身及各区域脂肪和肌肉质量与心血管疾病(CVD)和非CVD死亡率之间的关系:方法:在1999-2006年全国健康与营养调查中,选取了1417名年龄≥50岁的2型糖尿病成人。采用双能 X 射线吸收测量法得出全身、躯干、手臂和腿部脂肪量和肌肉量指数(FMI 和 MMI)。截至 2019 年 12 月 31 日的死亡率数据来自国家死亡指数。根据 Cox 比例危险模型估算出危险比(HRs)和 95% 置信区间(CIs):本研究共纳入 1417 名参与者(加权平均年龄 [标准误差]:63.7 [0.3] 岁;50.5% 为女性)。中位随访时间为 13.6 年,共记录了 797 例死亡(371 例心血管疾病相关死亡和 426 例非心血管疾病相关死亡)。手臂的 FMI 值越高,非心血管疾病死亡风险越高(第四四分位数 [Q4] 与第一四分位数 [Q1]:HR 1.82 [95% CI 1.13-2.94]),而躯干或腿部的 FMI 值越高,与心血管疾病或非心血管疾病死亡的关系不大。相反,手臂MMI越高,心血管疾病(Q4 vs. Q1:HR 0.51 [95% CI 0.33-0.81])和非心血管疾病(Q4 vs. Q1:HR 0.56 [95% CI 0.33-0.94])死亡风险越低。吸烟状况和臂部 FMI 对非心血管疾病死亡率有明显的交互作用(交互作用的 P = 0.007)。在目前或曾经吸烟者中,较高的手臂FMI与较高的非心血管疾病死亡风险相关(Q4 vs. Q1:HR 2.67 [95% CI 1.46-4.88]),但与非吸烟者无关(Q4 vs. Q1:HR 0.85 [95% CI 0.49-1.47]):结论:脂肪量和肌肉量(尤其是手臂肌肉量)与 T2D 患者的心血管疾病和非心血管疾病死亡率的相关性不同。我们的发现强调了手臂的身体成分在预测患有 T2D 的老年人死亡率方面的预测价值。
{"title":"Differential impacts of fat and muscle mass on cardiovascular and non-cardiovascular mortality in individuals with type 2 diabetes.","authors":"Jie Guo, Yuxia Wei, Emerald G Heiland, Anna Marseglia","doi":"10.1002/jcsm.13542","DOIUrl":"https://doi.org/10.1002/jcsm.13542","url":null,"abstract":"<p><strong>Background: </strong>The distribution of fat and muscle mass in different regions of the body can reflect different pathways to mortality in individuals with diabetes. Therefore, we investigated the associations between whole-body and regional body fat and muscle mass with cardiovascular disease (CVD) and non-CVD mortality in type 2 diabetes (T2D).</p><p><strong>Methods: </strong>Within the National Health and Nutrition Examination Survey 1999-2006, 1417 adults aged ≥50 years with T2D were selected. Dual-energy X-ray absorptiometry was used to derive whole-body, trunk, arm, and leg fat mass and muscle mass indices (FMI and MMI). Mortality data until 31 December 2019 were retrieved from the National Death Index. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated from Cox proportional hazard models.</p><p><strong>Results: </strong>A total of 1417 participants were included in this study (weighted mean age [standard error]: 63.7 [0.3] years; 50.5% female). Over a median follow-up of 13.6 years, 797 deaths were recorded (371 CVD-related and 426 non-CVD deaths). Higher FMI in the arm was associated with increased risk of non-CVD mortality (fourth quartile [Q4] vs. first quartile [Q1]: HR 1.82 [95% CI 1.13-2.94]), whereas higher FMI in the trunk or leg was not significantly associated with CVD or non-CVD mortality. Conversely, higher arm MMI was associated with a lower risk of both CVD (Q4 vs. Q1: HR 0.51 [95% CI 0.33-0.81]) and non-CVD (Q4 vs. Q1: HR 0.56 [95% CI 0.33-0.94]) mortality. There was a significant interaction between smoking status and arm FMI on non-CVD mortality (P for interaction = 0.007). Higher arm FMI was associated with a higher risk of non-CVD mortality among current or former smokers (Q4 vs. Q1: HR 2.67 [95% CI 1.46-4.88]) but not non-smokers (Q4 vs. Q1: HR 0.85 [95% CI 0.49-1.47]).</p><p><strong>Conclusions: </strong>Fat mass and muscle mass, especially in the arm, are differently associated with CVD and non-CVD mortality in people with T2D. Our findings underscore the predictive value of body compositions in the arm in forecasting mortality among older adults with T2D.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":null,"pages":null},"PeriodicalIF":8.9,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141597977","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: Sarcopenia, the age-related loss of muscle mass and function, brings multiple adverse outcomes including disability and death. Several sarcopenia consensuses have newly introduced the premorbid concept of possible sarcopenia and recommended early lifestyle interventions. Bidirectional transitions of premorbid states have been revealed in several chronic diseases yet not clarified in sarcopenia. This study aims to investigate the underlying transition patterns of sarcopenia states.
Methods: The study utilized three waves of data from a nationally representative survey, the China Health and Retirement Longitudinal Study (CHARLS), and included community-dwelling individuals aged 60 years and older with at least two sarcopenia states assessments based on the Asian Working Group for Sarcopenia criteria 2019 (AWGS2019) between 2011 and 2015. The estimated transition intensity and probability between non-sarcopenia, possible sarcopenia, sarcopenia, and death were investigated using multi-stage Markov (MSM) models.
Results: The study comprised 4395 individuals (49.2% female, median age 67 years) with a total of 10 778 records of sarcopenia state assessment, and the mean follow-up period was 3.29 years. A total of 24.5% of individuals with a current state of possible sarcopenia returned to non-sarcopenia, 60.3% remained possible sarcopenia, 6.7% progressed to sarcopenia, and 8.5% died by the next follow-up. The transition intensity of recovery to non-sarcopenia (0.252, 95% CI 0.231-0.275) was 2.8 times greater than the deterioration to sarcopenia (0.090, 95% CI 0.080-0.100) for individuals with possible sarcopenia. For individuals with possible sarcopenia, the estimated probabilities of recovering to non-sarcopenia, progressing to sarcopenia, and transitioning to death within a 1-year observation were 0.181, 0.066, and 0.035, respectively. For individuals with sarcopenia, the estimated probabilities of recovering to non-sarcopenia, recovering to possible sarcopenia, and transitioning to death within 1-year observation were 0.016, 0.125, and 0.075, respectively. In covariables analysis, age, sex, body mass index, physical function impairment, smoking, hypertension, and diabetes are important factors influencing bidirectional transitions.
Conclusions: The findings highlight the bidirectional transitions of sarcopenia states among older adults and reveal a notable proportion of possible sarcopenia show potential for recovery in the natural course. Screening and intensifying interventions based on risk factors may facilitate a recovery transition.
背景:肌肉疏松症是与年龄有关的肌肉质量和功能丧失,会带来多种不良后果,包括残疾和死亡。一些 "肌肉疏松症 "共识新近提出了可能出现 "肌肉疏松症 "的病前概念,并建议尽早采取生活方式干预措施。多种慢性疾病都存在病前状态的双向转换,但在肌肉疏松症中却未得到明确。本研究旨在探讨肌肉疏松症状态的基本转变模式:本研究利用中国健康与退休纵向研究(CHARLS)的三波全国代表性调查数据,纳入了2011年至2015年间根据亚洲肌少症工作组2019年标准(AWGS2019)至少评估过两种肌少症状态的60岁及以上社区居民。使用多阶段马尔可夫(MSM)模型研究了非肌肉疏松症、可能的肌肉疏松症、肌肉疏松症和死亡之间的估计过渡强度和概率:该研究共收集了4395人(49.2%为女性,中位年龄为67岁)的10 778条肌肉疏松症状态评估记录,平均随访时间为3.29年。在目前可能患有肌肉疏松症的人中,共有24.5%的人在下次随访时恢复到非肌肉疏松症状态,60.3%的人仍可能患有肌肉疏松症,6.7%的人发展为肌肉疏松症,8.5%的人死亡。对于可能患有肌肉疏松症的人来说,恢复到非肌肉疏松症的转变强度(0.252,95% CI 0.231-0.275)是恶化到肌肉疏松症的转变强度(0.090,95% CI 0.080-0.100)的 2.8 倍。对于可能患有肌肉疏松症的患者,在1年的观察期内恢复到非肌肉疏松症、进展到肌肉疏松症以及转为死亡的估计概率分别为0.181、0.066和0.035。对于患有肌肉疏松症的个体,在1年观察期内恢复为非肌肉疏松症、恢复为可能的肌肉疏松症以及转变为死亡的估计概率分别为0.016、0.125和0.075。在协变量分析中,年龄、性别、体重指数、身体功能障碍、吸烟、高血压和糖尿病是影响双向转归的重要因素:研究结果凸显了老年人肌肉疏松症状态的双向转变,并揭示了相当一部分可能的肌肉疏松症患者在自然病程中显示出恢复的潜力。根据风险因素进行筛查并加强干预措施可促进恢复过渡。
{"title":"Bidirectional transitions of sarcopenia states in older adults: The longitudinal evidence from CHARLS.","authors":"Ya-Xi Luo, Xiao-Han Zhou, Tian Heng, Ling-Ling Yang, Ying-Hai Zhu, Peng Hu, Xiu-Qing Yao","doi":"10.1002/jcsm.13541","DOIUrl":"https://doi.org/10.1002/jcsm.13541","url":null,"abstract":"<p><strong>Background: </strong>Sarcopenia, the age-related loss of muscle mass and function, brings multiple adverse outcomes including disability and death. Several sarcopenia consensuses have newly introduced the premorbid concept of possible sarcopenia and recommended early lifestyle interventions. Bidirectional transitions of premorbid states have been revealed in several chronic diseases yet not clarified in sarcopenia. This study aims to investigate the underlying transition patterns of sarcopenia states.</p><p><strong>Methods: </strong>The study utilized three waves of data from a nationally representative survey, the China Health and Retirement Longitudinal Study (CHARLS), and included community-dwelling individuals aged 60 years and older with at least two sarcopenia states assessments based on the Asian Working Group for Sarcopenia criteria 2019 (AWGS2019) between 2011 and 2015. The estimated transition intensity and probability between non-sarcopenia, possible sarcopenia, sarcopenia, and death were investigated using multi-stage Markov (MSM) models.</p><p><strong>Results: </strong>The study comprised 4395 individuals (49.2% female, median age 67 years) with a total of 10 778 records of sarcopenia state assessment, and the mean follow-up period was 3.29 years. A total of 24.5% of individuals with a current state of possible sarcopenia returned to non-sarcopenia, 60.3% remained possible sarcopenia, 6.7% progressed to sarcopenia, and 8.5% died by the next follow-up. The transition intensity of recovery to non-sarcopenia (0.252, 95% CI 0.231-0.275) was 2.8 times greater than the deterioration to sarcopenia (0.090, 95% CI 0.080-0.100) for individuals with possible sarcopenia. For individuals with possible sarcopenia, the estimated probabilities of recovering to non-sarcopenia, progressing to sarcopenia, and transitioning to death within a 1-year observation were 0.181, 0.066, and 0.035, respectively. For individuals with sarcopenia, the estimated probabilities of recovering to non-sarcopenia, recovering to possible sarcopenia, and transitioning to death within 1-year observation were 0.016, 0.125, and 0.075, respectively. In covariables analysis, age, sex, body mass index, physical function impairment, smoking, hypertension, and diabetes are important factors influencing bidirectional transitions.</p><p><strong>Conclusions: </strong>The findings highlight the bidirectional transitions of sarcopenia states among older adults and reveal a notable proportion of possible sarcopenia show potential for recovery in the natural course. Screening and intensifying interventions based on risk factors may facilitate a recovery transition.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":null,"pages":null},"PeriodicalIF":8.9,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141597976","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}
Mao-Yuan Wang, Jia-Ming Yang, Yi Wu, Hai Li, Yan-Biao Zhong, Yun Luo, Rui-Lian Xie
Background: Skeletal muscle injury is one of the most common sports injuries; if not properly treated or not effective rehabilitation treatment after injury, it can be transformed into chronic cumulative injury. Curcumin, an herbal ingredient, has been found to promote skeletal muscle injury repair and regeneration. The Wnt5a pathway is related to the expression of myogenic regulatory factors, and Ca2+ promotes the differentiation and fusion process of myoblasts. This study explored the effect and mechanism of curcumin on myoblast differentiation during the repair and regeneration of injured skeletal muscle and its relationship with the Wnt5a pathway and Ca2+ channel.
Methods: Myogenic differentiation of C2C12 cells was induced with 2% horse serum, and a mouse (male, 10 weeks old) model of acute skeletal muscle injury was established using cardiotoxin (20 μL). In addition, we constructed a Wnt5a knockdown C2C12 cell model and a Wnt5a knockout mouse model. Besides, curcumin was added to the cell culture solution (80 mg/L) and fed to the mice (50 mg/kg). Fluorescence microscopy was used to determine the concentration of Ca2+. Western blot and RT-qPCR were used to detect the protein and mRNA levels of Wnt5a, CaN, NFAT2, MyoD, Myf5, Pax7, and Myogenin. The expression levels of MyoD, Myf5, Myogenin, MHC, Desmin, and NFAT2 were detected using immunofluorescence techniques. In addition, MyoD expression was observed using immunohistochemistry, and morphological changes in mouse muscle tissue were observed using HE staining.
Results: During myoblast differentiation and muscle regeneration, Wnt5a expression was upregulated (P < 0.001) and the Wnt5a signalling pathway was activated. Wnt5a overexpression promoted the expression of MyoD, Myf5, Myogenin, MHC, and Desmin (P < 0.05), and conversely, knockdown of Wnt5a inhibited their expression (P < 0.001). The Wnt5a pathway mediated the opening of Ca2+ channels, regulated the expression levels of CaN, NFAT2, MyoD, Myf5, Myogenin, MHC, and Desmin (P < 0.01) and promoted the differentiation of C2C12 myoblasts and the repair and regeneration of injured skeletal muscle. The expression of Wnt5a, CaN, NFAT2, MyoD, Myogenin, Myf5, and MHC in C2C12 myoblast was significantly increased after curcumin intervention (P < 0.05); however, their expression decreased significantly after knocking down Wnt5a on the basis of curcumin intervention (P < 0.05). Similarly, in Wnt5a knockout mice, the promotion of muscle regeneration by curcumin was significantly attenuated.
Conclusions: Curcumin can activate the Wnt5a signalling pathway and mediate the opening of Ca2+ channels to accelerate the myogenic differentiation of C2C12 cells and the repair and regeneration of injured skeletal muscle.
{"title":"Curcumin-activated Wnt5a pathway mediates Ca<sup>2+</sup> channel opening to affect myoblast differentiation and skeletal muscle regeneration.","authors":"Mao-Yuan Wang, Jia-Ming Yang, Yi Wu, Hai Li, Yan-Biao Zhong, Yun Luo, Rui-Lian Xie","doi":"10.1002/jcsm.13535","DOIUrl":"https://doi.org/10.1002/jcsm.13535","url":null,"abstract":"<p><strong>Background: </strong>Skeletal muscle injury is one of the most common sports injuries; if not properly treated or not effective rehabilitation treatment after injury, it can be transformed into chronic cumulative injury. Curcumin, an herbal ingredient, has been found to promote skeletal muscle injury repair and regeneration. The Wnt5a pathway is related to the expression of myogenic regulatory factors, and Ca<sup>2+</sup> promotes the differentiation and fusion process of myoblasts. This study explored the effect and mechanism of curcumin on myoblast differentiation during the repair and regeneration of injured skeletal muscle and its relationship with the Wnt5a pathway and Ca<sup>2+</sup> channel.</p><p><strong>Methods: </strong>Myogenic differentiation of C2C12 cells was induced with 2% horse serum, and a mouse (male, 10 weeks old) model of acute skeletal muscle injury was established using cardiotoxin (20 μL). In addition, we constructed a Wnt5a knockdown C2C12 cell model and a Wnt5a knockout mouse model. Besides, curcumin was added to the cell culture solution (80 mg/L) and fed to the mice (50 mg/kg). Fluorescence microscopy was used to determine the concentration of Ca<sup>2+</sup>. Western blot and RT-qPCR were used to detect the protein and mRNA levels of Wnt5a, CaN, NFAT2, MyoD, Myf5, Pax7, and Myogenin. The expression levels of MyoD, Myf5, Myogenin, MHC, Desmin, and NFAT2 were detected using immunofluorescence techniques. In addition, MyoD expression was observed using immunohistochemistry, and morphological changes in mouse muscle tissue were observed using HE staining.</p><p><strong>Results: </strong>During myoblast differentiation and muscle regeneration, Wnt5a expression was upregulated (P < 0.001) and the Wnt5a signalling pathway was activated. Wnt5a overexpression promoted the expression of MyoD, Myf5, Myogenin, MHC, and Desmin (P < 0.05), and conversely, knockdown of Wnt5a inhibited their expression (P < 0.001). The Wnt5a pathway mediated the opening of Ca<sup>2+</sup> channels, regulated the expression levels of CaN, NFAT2, MyoD, Myf5, Myogenin, MHC, and Desmin (P < 0.01) and promoted the differentiation of C2C12 myoblasts and the repair and regeneration of injured skeletal muscle. The expression of Wnt5a, CaN, NFAT2, MyoD, Myogenin, Myf5, and MHC in C2C12 myoblast was significantly increased after curcumin intervention (P < 0.05); however, their expression decreased significantly after knocking down Wnt5a on the basis of curcumin intervention (P < 0.05). Similarly, in Wnt5a knockout mice, the promotion of muscle regeneration by curcumin was significantly attenuated.</p><p><strong>Conclusions: </strong>Curcumin can activate the Wnt5a signalling pathway and mediate the opening of Ca<sup>2+</sup> channels to accelerate the myogenic differentiation of C2C12 cells and the repair and regeneration of injured skeletal muscle.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":null,"pages":null},"PeriodicalIF":8.9,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141562177","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}
Shu Yang, Lijiao Xiong, Guangyan Yang, Jiaqing Xiang, Lixing Li, Lin Kang, Zhen Liang
Background: Muscle atrophy can cause muscle dysfunction and weakness. Krüppel-like factor 13 (KLF13), a central regulator of cellular energy metabolism, is highly expressed in skeletal muscles and implicated in the pathogenesis of several diseases. This study investigated the role of KLF13 in muscle atrophy, which could be a novel therapeutic target.
Methods: The effects of gene knockdown and pharmacological targeting of KLF13 on skeletal muscle atrophy were investigated using cell-based and animal models. Clofoctol, an antibiotic and KLF13 agonist, was also investigated as a candidate for repurposing. The mechanisms related to skeletal muscle atrophy were assessed by measuring the expression levels and activation statuses of key regulatory pathways and validated using gene knockdown and RNA sequencing.
Results: In a dexamethasone-induced muscle atrophy mouse model, the KLF13 knockout group had decreased muscle strength (N) (1.77 ± 0.10 vs. 1.48 ± 0.16, P < 0.01), muscle weight (%) [gastrocnemius (Gas): 76.0 ± 5.69 vs. 60.7 ± 7.23, P < 0.001; tibialis anterior (TA): 75.8 ± 6.21 vs. 67.5 ± 5.01, P < 0.05], and exhaustive running distance (m) (495.5 ± 64.8 vs. 315.5 ± 60.9, P < 0.05) compared with the control group. KLF13 overexpression preserved muscle mass (Gas: 100 ± 6.38 vs. 120 ± 14.4, P < 0.01) and the exhaustive running distance (423.8 ± 59.04 vs. 530.2 ± 77.45, P < 0.05) in an in vivo diabetes-induced skeletal muscle atrophy model. Clofoctol treatment protected against dexamethasone-induced muscle atrophy. Myotubes treated with dexamethasone, an atrophy-inducing glucocorticoid, were aggravated by KLF13 knockout, but anti-atrophic effects were achieved by inducing KLF13 overexpression. We performed a transcriptome analysis and luciferase reporter assays to further explore this mechanism, finding that delta-like 4 (Dll4) was a novel target gene of KLF13. The KLF13 transcript repressed Dll4, inhibiting the Dll4-Notch2 axis and preventing muscle atrophy. Dexamethasone inhibited KLF13 expression by inhibiting myogenic differentiation 1 (i.e., MYOD1)-mediated KLF13 transcriptional activation and promoting F-Box and WD repeat domain containing 7 (i.e., FBXW7)-mediated KLF13 ubiquitination.
Conclusions: This study sheds new light on the mechanisms underlying skeletal muscle atrophy and potential drug targets. KLF13 regulates muscle atrophy and is a potential therapeutic target. Clofoctol is an attractive compound for repurposing studies to treat skeletal muscle atrophy.
背景:肌肉萎缩可导致肌肉功能障碍和虚弱。Krüppel样因子13(KLF13)是细胞能量代谢的核心调节因子,在骨骼肌中高表达,与多种疾病的发病机制有关。本研究探讨了 KLF13 在肌肉萎缩中的作用,这可能是一个新的治疗靶点:方法:利用细胞模型和动物模型研究了基因敲除和药物靶向 KLF13 对骨骼肌萎缩的影响。研究还将抗生素和KLF13激动剂Clofoctol作为候选药物进行了再利用研究。通过测量关键调控通路的表达水平和激活状态评估了与骨骼肌萎缩有关的机制,并使用基因敲除和 RNA 测序进行了验证:结果:在地塞米松诱导的肌肉萎缩小鼠模型中,KLF13基因敲除组的肌力(N)下降(1.77 ± 0.10 vs. 1.48 ± 0.16,P 结论:KLF13基因敲除组的肌力(N)下降(1.77 ± 0.10 vs. 1.48 ± 0.16,P):本研究揭示了骨骼肌萎缩的机制和潜在的药物靶点。KLF13调控肌肉萎缩,是一个潜在的治疗靶点。Clofoctol是一种有吸引力的化合物,可用于治疗骨骼肌萎缩的再利用研究。
{"title":"KLF13 restrains Dll4-muscular Notch2 axis to improve the muscle atrophy.","authors":"Shu Yang, Lijiao Xiong, Guangyan Yang, Jiaqing Xiang, Lixing Li, Lin Kang, Zhen Liang","doi":"10.1002/jcsm.13538","DOIUrl":"https://doi.org/10.1002/jcsm.13538","url":null,"abstract":"<p><strong>Background: </strong>Muscle atrophy can cause muscle dysfunction and weakness. Krüppel-like factor 13 (KLF13), a central regulator of cellular energy metabolism, is highly expressed in skeletal muscles and implicated in the pathogenesis of several diseases. This study investigated the role of KLF13 in muscle atrophy, which could be a novel therapeutic target.</p><p><strong>Methods: </strong>The effects of gene knockdown and pharmacological targeting of KLF13 on skeletal muscle atrophy were investigated using cell-based and animal models. Clofoctol, an antibiotic and KLF13 agonist, was also investigated as a candidate for repurposing. The mechanisms related to skeletal muscle atrophy were assessed by measuring the expression levels and activation statuses of key regulatory pathways and validated using gene knockdown and RNA sequencing.</p><p><strong>Results: </strong>In a dexamethasone-induced muscle atrophy mouse model, the KLF13 knockout group had decreased muscle strength (N) (1.77 ± 0.10 vs. 1.48 ± 0.16, P < 0.01), muscle weight (%) [gastrocnemius (Gas): 76.0 ± 5.69 vs. 60.7 ± 7.23, P < 0.001; tibialis anterior (TA): 75.8 ± 6.21 vs. 67.5 ± 5.01, P < 0.05], and exhaustive running distance (m) (495.5 ± 64.8 vs. 315.5 ± 60.9, P < 0.05) compared with the control group. KLF13 overexpression preserved muscle mass (Gas: 100 ± 6.38 vs. 120 ± 14.4, P < 0.01) and the exhaustive running distance (423.8 ± 59.04 vs. 530.2 ± 77.45, P < 0.05) in an in vivo diabetes-induced skeletal muscle atrophy model. Clofoctol treatment protected against dexamethasone-induced muscle atrophy. Myotubes treated with dexamethasone, an atrophy-inducing glucocorticoid, were aggravated by KLF13 knockout, but anti-atrophic effects were achieved by inducing KLF13 overexpression. We performed a transcriptome analysis and luciferase reporter assays to further explore this mechanism, finding that delta-like 4 (Dll4) was a novel target gene of KLF13. The KLF13 transcript repressed Dll4, inhibiting the Dll4-Notch2 axis and preventing muscle atrophy. Dexamethasone inhibited KLF13 expression by inhibiting myogenic differentiation 1 (i.e., MYOD1)-mediated KLF13 transcriptional activation and promoting F-Box and WD repeat domain containing 7 (i.e., FBXW7)-mediated KLF13 ubiquitination.</p><p><strong>Conclusions: </strong>This study sheds new light on the mechanisms underlying skeletal muscle atrophy and potential drug targets. KLF13 regulates muscle atrophy and is a potential therapeutic target. Clofoctol is an attractive compound for repurposing studies to treat skeletal muscle atrophy.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":null,"pages":null},"PeriodicalIF":8.9,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141553820","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}
Wouter R P H van de Worp, Jan Theys, Cecile J A Wolfs, Frank Verhaegen, Annemie M W J Schols, Ardy van Helvoort, Ramon C J Langen
Background: Cachexia, a syndrome with high prevalence in non-small cell lung cancer patients, impairs quality of life and reduces tolerance and responsiveness to cancer therapy resulting in decreased survival. Optimal nutritional care is pivotal in the treatment of cachexia and a recommended cornerstone of multimodal therapy. Here, we investigated the therapeutic effect of an intervention diet consisting of a specific combination of high protein, leucine, fish oil, vitamin D, galacto-oligosaccharides, and fructo-oligosaccharides on the development and progression of cachexia in an orthotopic lung cancer mouse model.
Methods: Eleven-week-old male 129S2/Sv mice were orthotopically implanted with 344P lung epithelial tumour cells or vehicle (control). Seven days post-implantation tumour-bearing (TB) mice were allocated to either intervention- or isocaloric control diet. Cachexia was defined as 5 days of consecutive body weight loss, after which mice were euthanized for tissue analyses.
Results: TB mice developed cachexia accompanied by significant loss of skeletal muscle mass and epididymal fat mass compared with sham operated mice. The cachectic endpoint was significantly delayed (46.0 ± 15.2 vs. 34.7 ± 11.4 days), and the amount (-1.57 ± 0.62 vs. -2.13 ± 0.57 g) and progression (-0.26 ± 0.14 vs. -0.39 ± 0.11 g/day) of body weight loss were significantly reduced by the intervention compared with control diet. Moreover, systemic inflammation (pentraxin-2 plasma levels) and alterations in molecular markers for proteolysis and protein synthesis, indicative of muscle atrophy signalling in TB-mice, were suppressed in skeletal muscle by the intervention diet.
Conclusions: Together, these data demonstrate the potential of this multinutrient intervention, targeting multiple components of cachexia, as integral part of lung cancer management.
背景:恶病质是一种在非小细胞肺癌患者中发病率很高的综合征,会损害患者的生活质量,降低患者对癌症治疗的耐受性和反应性,从而导致生存率下降。最佳营养护理是治疗恶病质的关键,也是多模式疗法的推荐基石。在此,我们研究了由高蛋白、亮氨酸、鱼油、维生素 D、半乳糖寡糖和果糖寡糖的特定组合组成的干预饮食对正位肺癌小鼠模型中恶病质的发生和发展的治疗效果:11周大的雄性129S2/Sv小鼠被正位植入344P肺上皮肿瘤细胞或载体(对照组)。植入后七天,肿瘤携带(TB)小鼠被分配到干预饮食或等热量对照饮食中。连续5天体重下降即为恶病质,之后小鼠被安乐死以进行组织分析:结果:与假手术小鼠相比,肺结核小鼠出现恶病质,并伴有骨骼肌质量和附睾脂肪质量的显著下降。与对照组相比,干预后小鼠的恶病质终点明显推迟(46.0 ± 15.2 天 vs. 34.7 ± 11.4 天),体重下降的数量(-1.57 ± 0.62 克 vs. -2.13 ± 0.57 克)和进展(-0.26 ± 0.14 克 vs. -0.39 ± 0.11 克/天)明显减少。此外,干预饮食还抑制了骨骼肌中的全身炎症(五肽-2 血浆水平)以及蛋白质分解和蛋白质合成分子标志物的改变,这些都表明结核病小鼠肌肉萎缩的信号:总之,这些数据证明了这种针对恶病质多种成分的多营养素干预方法的潜力,是肺癌治疗不可或缺的一部分。
{"title":"Targeted nutritional intervention attenuates experimental lung cancer cachexia.","authors":"Wouter R P H van de Worp, Jan Theys, Cecile J A Wolfs, Frank Verhaegen, Annemie M W J Schols, Ardy van Helvoort, Ramon C J Langen","doi":"10.1002/jcsm.13520","DOIUrl":"https://doi.org/10.1002/jcsm.13520","url":null,"abstract":"<p><strong>Background: </strong>Cachexia, a syndrome with high prevalence in non-small cell lung cancer patients, impairs quality of life and reduces tolerance and responsiveness to cancer therapy resulting in decreased survival. Optimal nutritional care is pivotal in the treatment of cachexia and a recommended cornerstone of multimodal therapy. Here, we investigated the therapeutic effect of an intervention diet consisting of a specific combination of high protein, leucine, fish oil, vitamin D, galacto-oligosaccharides, and fructo-oligosaccharides on the development and progression of cachexia in an orthotopic lung cancer mouse model.</p><p><strong>Methods: </strong>Eleven-week-old male 129S2/Sv mice were orthotopically implanted with 344P lung epithelial tumour cells or vehicle (control). Seven days post-implantation tumour-bearing (TB) mice were allocated to either intervention- or isocaloric control diet. Cachexia was defined as 5 days of consecutive body weight loss, after which mice were euthanized for tissue analyses.</p><p><strong>Results: </strong>TB mice developed cachexia accompanied by significant loss of skeletal muscle mass and epididymal fat mass compared with sham operated mice. The cachectic endpoint was significantly delayed (46.0 ± 15.2 vs. 34.7 ± 11.4 days), and the amount (-1.57 ± 0.62 vs. -2.13 ± 0.57 g) and progression (-0.26 ± 0.14 vs. -0.39 ± 0.11 g/day) of body weight loss were significantly reduced by the intervention compared with control diet. Moreover, systemic inflammation (pentraxin-2 plasma levels) and alterations in molecular markers for proteolysis and protein synthesis, indicative of muscle atrophy signalling in TB-mice, were suppressed in skeletal muscle by the intervention diet.</p><p><strong>Conclusions: </strong>Together, these data demonstrate the potential of this multinutrient intervention, targeting multiple components of cachexia, as integral part of lung cancer management.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":null,"pages":null},"PeriodicalIF":8.9,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141533025","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}
Xi Wang, Liwang Gao, Jingfan Xiong, Hong Cheng, Li Liu, Hongbo Dong, Yiwen Huang, Hongmin Fan, Xia Wang, Xinying Shan, Pei Xiao, Junting Liu, Yinkun Yan, Jie Mi
Background: Sarcopenia is an important indicator of ill health and is linked to increased mortality and a reduced quality of life. Age-associated muscle mass indices provide a critical tool to help understand the development of sarcopenia. This study aimed to develop sex- and age-specific percentiles for muscle mass indices in a Chinese population and to compare those indices with those from other ethnicities using the National Health and Nutrition Examination Survey (NHANES) data.
Methods: Whole-body and regional muscle mass was measured by dual-energy X-ray absorptiometry (DXA) in participants of the China Body Composition Life-course (BCL) study (17 203 healthy Chinese aged 3-60 years, male 48.9%) and NHANES (12 663 healthy Americans aged 8-59 years, male 50.4%). Age- and sex-specific percentile curves were generated for whole-body muscle mass and appendicular skeletal muscle mass using the Generalized Additive Model for Location Scale and Shape statistical method.
Results: Values of upper and lower muscle mass across ages had three periods: an increase from age 3 to a peak at age 25 in males (with the 5th and 95th values of 41.5 and 66.4 kg, respectively) and age 23 in females (with the 5th and 95th values of 28.4 and 45.1 kg, respectively), a plateau through midlife (30s-50s) and then a decline after their early 50s. The age at which muscle mass began to decline was 52 years in men with the 5th and 95th percentile values of 43.5 and 64.6 kg, and 51 years in women with the 5th and 95th percentile values of 31.6 and 46.9 kg. Appendicular skeletal muscle mass decreased earlier than whole body muscle mass, especially leg skeletal muscle mass, which decreased slightly after age 49 years in both sexes. In comparison with their US counterparts in the NHANES, the Chinese participants had lower muscle mass indices (all P < 0.001) and reached a muscle mass peak earlier with a lower muscle mass, with the exception of similar values compared with adult Mexican and White participants. The muscle mass growth rate of Chinese children decreased faster than that of other races after the age of 13.
Conclusions: We present the sex- and age-specific percentiles for muscle mass and appendicular skeletal muscle mass by DXA in participants aged 3-60 from China and compare them with those of different ethnic groups in NHANES. The rich data characterize the trajectories of key muscle mass indices that may facilitate the clinical appraisal of muscle mass and improve the early diagnosis of sarcopenia in the Chinese population.
{"title":"The life-course changes in muscle mass using dual-energy X-ray absorptiometry: The China BCL study and the US NHANES study.","authors":"Xi Wang, Liwang Gao, Jingfan Xiong, Hong Cheng, Li Liu, Hongbo Dong, Yiwen Huang, Hongmin Fan, Xia Wang, Xinying Shan, Pei Xiao, Junting Liu, Yinkun Yan, Jie Mi","doi":"10.1002/jcsm.13522","DOIUrl":"https://doi.org/10.1002/jcsm.13522","url":null,"abstract":"<p><strong>Background: </strong>Sarcopenia is an important indicator of ill health and is linked to increased mortality and a reduced quality of life. Age-associated muscle mass indices provide a critical tool to help understand the development of sarcopenia. This study aimed to develop sex- and age-specific percentiles for muscle mass indices in a Chinese population and to compare those indices with those from other ethnicities using the National Health and Nutrition Examination Survey (NHANES) data.</p><p><strong>Methods: </strong>Whole-body and regional muscle mass was measured by dual-energy X-ray absorptiometry (DXA) in participants of the China Body Composition Life-course (BCL) study (17 203 healthy Chinese aged 3-60 years, male 48.9%) and NHANES (12 663 healthy Americans aged 8-59 years, male 50.4%). Age- and sex-specific percentile curves were generated for whole-body muscle mass and appendicular skeletal muscle mass using the Generalized Additive Model for Location Scale and Shape statistical method.</p><p><strong>Results: </strong>Values of upper and lower muscle mass across ages had three periods: an increase from age 3 to a peak at age 25 in males (with the 5th and 95th values of 41.5 and 66.4 kg, respectively) and age 23 in females (with the 5th and 95th values of 28.4 and 45.1 kg, respectively), a plateau through midlife (30s-50s) and then a decline after their early 50s. The age at which muscle mass began to decline was 52 years in men with the 5th and 95th percentile values of 43.5 and 64.6 kg, and 51 years in women with the 5th and 95th percentile values of 31.6 and 46.9 kg. Appendicular skeletal muscle mass decreased earlier than whole body muscle mass, especially leg skeletal muscle mass, which decreased slightly after age 49 years in both sexes. In comparison with their US counterparts in the NHANES, the Chinese participants had lower muscle mass indices (all P < 0.001) and reached a muscle mass peak earlier with a lower muscle mass, with the exception of similar values compared with adult Mexican and White participants. The muscle mass growth rate of Chinese children decreased faster than that of other races after the age of 13.</p><p><strong>Conclusions: </strong>We present the sex- and age-specific percentiles for muscle mass and appendicular skeletal muscle mass by DXA in participants aged 3-60 from China and compare them with those of different ethnic groups in NHANES. The rich data characterize the trajectories of key muscle mass indices that may facilitate the clinical appraisal of muscle mass and improve the early diagnosis of sarcopenia in the Chinese population.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":null,"pages":null},"PeriodicalIF":8.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141475549","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}