Pub Date : 2021-01-01Epub Date: 2020-12-28DOI: 10.1002/rco2.29
Gavin Pharaoh, Jacob Brown, Rojina Ranjit, Zoltan Ungvari, Holly Van Remmen
Background: Mitochondrial bioenergetics are sensitive to adenosine diphosphate (ADP) concentration. Reactive oxygen species (ROS) production and respiration [oxygen consumption rate (OCR)] are altered at physiological ADP concentrations (i.e. ADP insensitivity) in aged human muscle. Here, we investigate ADP sensitivity in mouse muscle mitochondria.
Methods: We measured OCR and ROS production in permeabilized gastrocnemius fibres using an ADP titration protocol and the Oroboros O2k respirometer and fluorometer. We measured changes in ADP sensitivity in muscle from mice at different ages, after sciatic nerve transection (denervation), and in response to increased oxidative stress (Sod1-/- mice). Further, we asked whether the mitochondrial-targeted peptide SS-31 can modulate ADP insensitivity and contractile function in the Sod1-/- mouse model.
Results: Reduced ADP sensitivity is associated with increases in mitochondrial ROS production in aged (62%) and Sod1-/- (33%) mice. The maximal capacity to produce ROS does not increase with age, and there is no effect of age on ADP sensitivity for OCR in mouse gastrocnemii. Denervation does not induce ADP insensitivity for either ROS generation or OCR. Treatment of Sod1-/- mice with SS-31 increases ADP sensitivity for both OCR and ROS, decreases maximal ROS production (~40%), and improves resistance to muscle fatigue.
Conclusions: Adenosine diphosphate sensitivity for ROS production decreases in aged mouse gastrocnemius muscle fibres, although aged mice do not exhibit a difference in OCR. Denervation does not induce ADP insensitivity; however, insensitivity to ADP is induced in a model of oxidative stress. ADP insensitivity could contribute to muscle fatigue, and SS-31 may be the first drug capable of targeting this aging phenotype.
{"title":"Reduced adenosine diphosphate sensitivity in skeletal muscle mitochondria increases reactive oxygen species production in mouse models of aging and oxidative stress but not denervation.","authors":"Gavin Pharaoh, Jacob Brown, Rojina Ranjit, Zoltan Ungvari, Holly Van Remmen","doi":"10.1002/rco2.29","DOIUrl":"10.1002/rco2.29","url":null,"abstract":"<p><strong>Background: </strong>Mitochondrial bioenergetics are sensitive to adenosine diphosphate (ADP) concentration. Reactive oxygen species (ROS) production and respiration [oxygen consumption rate (OCR)] are altered at physiological ADP concentrations (i.e. ADP insensitivity) in aged human muscle. Here, we investigate ADP sensitivity in mouse muscle mitochondria.</p><p><strong>Methods: </strong>We measured OCR and ROS production in permeabilized gastrocnemius fibres using an ADP titration protocol and the Oroboros O2k respirometer and fluorometer. We measured changes in ADP sensitivity in muscle from mice at different ages, after sciatic nerve transection (denervation), and in response to increased oxidative stress (<i>Sod1</i> <sup>-/-</sup> mice). Further, we asked whether the mitochondrial-targeted peptide SS-31 can modulate ADP insensitivity and contractile function in the <i>Sod1</i> <sup>-/-</sup> mouse model.</p><p><strong>Results: </strong>Reduced ADP sensitivity is associated with increases in mitochondrial ROS production in aged (62%) and <i>Sod1</i> <sup>-/-</sup> (33%) mice. The maximal capacity to produce ROS does not increase with age, and there is no effect of age on ADP sensitivity for OCR in mouse gastrocnemii. Denervation does not induce ADP insensitivity for either ROS generation or OCR. Treatment of <i>Sod1</i> <sup>-/-</sup> mice with SS-31 increases ADP sensitivity for both OCR and ROS, decreases maximal ROS production (<sup>~</sup>40%), and improves resistance to muscle fatigue.</p><p><strong>Conclusions: </strong>Adenosine diphosphate sensitivity for ROS production decreases in aged mouse gastrocnemius muscle fibres, although aged mice do not exhibit a difference in OCR. Denervation does not induce ADP insensitivity; however, insensitivity to ADP is induced in a model of oxidative stress. ADP insensitivity could contribute to muscle fatigue, and SS-31 may be the first drug capable of targeting this aging phenotype.</p>","PeriodicalId":73544,"journal":{"name":"JCSM rapid communications","volume":"4 1","pages":"75-89"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9503137/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33483970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Kanou, Katsuyuki Nakamura, Kyohei Horie, H. Sakai, Yuta Yanagihara, Iori Sakakibara, K. Yamana, Yuuki Imai
Muscle wasting is a common condition concomitant with aging. Androgens significantly increase skeletal muscle mass, but the role of the androgen receptor (AR) in skeletal muscle is not well established. TEI‐SARM2, a novel selective androgen receptor modulator (SARM), was developed as a pharmaceutical candidate for the treatment of muscle wasting diseases.
{"title":"Polyamine pathway is associated with muscle anabolic effects by androgen receptor ligand","authors":"M. Kanou, Katsuyuki Nakamura, Kyohei Horie, H. Sakai, Yuta Yanagihara, Iori Sakakibara, K. Yamana, Yuuki Imai","doi":"10.1002/rco2.28","DOIUrl":"https://doi.org/10.1002/rco2.28","url":null,"abstract":"Muscle wasting is a common condition concomitant with aging. Androgens significantly increase skeletal muscle mass, but the role of the androgen receptor (AR) in skeletal muscle is not well established. TEI‐SARM2, a novel selective androgen receptor modulator (SARM), was developed as a pharmaceutical candidate for the treatment of muscle wasting diseases.","PeriodicalId":73544,"journal":{"name":"JCSM rapid communications","volume":"4 1","pages":"57 - 74"},"PeriodicalIF":0.0,"publicationDate":"2020-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/rco2.28","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47449637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
I. Churilov, L. Churilov, K. Brock, Navina Curtain, D. Murphy, Kavitha Muthukrishnan, R. MacIsaac, E. Ekinci
Despite the recommendation of European Working Group on Sarcopenia in Older People 2 (EWGSOP2) consensus statement not to exclude patients younger than 65 years, the prevalence of sarcopenia has not been investigated in younger post‐acute inpatient rehabilitation population. The objectives of this study were to: i) estimate the prevalence of sarcopenia in post‐acute inpatient rehabilitation population; ii) compare the prevalence of sarcopenia in patients above and below 65 years.
{"title":"The prevalence of sarcopenia in middle‐aged and older patients in post‐acute inpatient rehabilitation: a cross‐sectional study","authors":"I. Churilov, L. Churilov, K. Brock, Navina Curtain, D. Murphy, Kavitha Muthukrishnan, R. MacIsaac, E. Ekinci","doi":"10.1002/rco2.25","DOIUrl":"https://doi.org/10.1002/rco2.25","url":null,"abstract":"Despite the recommendation of European Working Group on Sarcopenia in Older People 2 (EWGSOP2) consensus statement not to exclude patients younger than 65 years, the prevalence of sarcopenia has not been investigated in younger post‐acute inpatient rehabilitation population. The objectives of this study were to: i) estimate the prevalence of sarcopenia in post‐acute inpatient rehabilitation population; ii) compare the prevalence of sarcopenia in patients above and below 65 years.","PeriodicalId":73544,"journal":{"name":"JCSM rapid communications","volume":"4 1","pages":"16 - 23"},"PeriodicalIF":0.0,"publicationDate":"2020-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/rco2.25","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49065803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gurpreet K. Arora, Arun Gupta, Tong Guo, Aakash Y. Gandhi, Aaron Laine, Dorothy L. Williams, Chul Ahn, Puneeth Iyengar, Rodney E. Infante
Background
Cachexia, a syndrome of muscle atrophy, adipose loss, and anorexia, is associated with reduced survival in cancer patients. The colon adenocarcinoma C26c20 cell line secretes the cytokine leukaemia inhibitory factor (LIF), which induces cachexia. We characterized how LIF promotes cachexia-associated weight loss and anorexia in mice through Janus kinase (JAK)-dependent changes in adipose and hypothalamic tissues.
Methods
Cachexia was induced in vivo with the heterotopic allotransplanted administration of C26c20 colon adenocarcinoma cells or the intraperitoneal administration of recombinant LIF in the absence or presence of JAK inhibitors. Blood, adipose, and hypothalamic tissues were collected and processed for cytokine/adipokine enzyme-linked immunosorbent assays, immunoblot analysis, and quantitative reverse transcription polymerase chain reaction (RT-PCR). Cachexia-associated lipolysis was induced in vitro by stimulating differentiated adipocytes with recombinant LIF or interleukin (IL)-6 in the absence or presence of lipase or JAK inhibitors. These adipocytes were processed for glycerol release into the media, immunoblot analysis, and RT-PCR.
Results
Tumour-secreted LIF induced changes in adipose tissue expression and serum levels of IL-6 and leptin in a JAK-dependent manner influencing cachexia-associated adipose wasting and anorexia. We identified two JAK inhibitors that block IL-6 family-mediated adipocyte lipolysis and IL-6 induction using an in vitro cachexia lipolysis assay. JAK inhibitors administered to the in vivo C26c20 cancer cachexia mouse models led to (i) a decrease in signal transducer and activator of transcription 3 phosphorylation in hypothalamic and adipose tissues, (ii) a reverse in the cachexia serum cytokine/adipokine signature, (iii) a delay in cancer cachexia-associated anorexia and adipose loss, and (iv) an improvement in overall survival.
Conclusions
JAK inhibitors suppress LIF-associated adipose loss and anorexia in both in vitro and in vivo models of cancer cachexia.
{"title":"Janus kinase inhibitors suppress cancer cachexia-associated anorexia and adipose wasting in mice","authors":"Gurpreet K. Arora, Arun Gupta, Tong Guo, Aakash Y. Gandhi, Aaron Laine, Dorothy L. Williams, Chul Ahn, Puneeth Iyengar, Rodney E. Infante","doi":"10.1002/rco2.24","DOIUrl":"https://doi.org/10.1002/rco2.24","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Cachexia, a syndrome of muscle atrophy, adipose loss, and anorexia, is associated with reduced survival in cancer patients. The colon adenocarcinoma C26c20 cell line secretes the cytokine leukaemia inhibitory factor (LIF), which induces cachexia. We characterized how LIF promotes cachexia-associated weight loss and anorexia in mice through Janus kinase (JAK)-dependent changes in adipose and hypothalamic tissues.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Cachexia was induced <i>in vivo</i> with the heterotopic allotransplanted administration of C26c20 colon adenocarcinoma cells or the intraperitoneal administration of recombinant LIF in the absence or presence of JAK inhibitors. Blood, adipose, and hypothalamic tissues were collected and processed for cytokine/adipokine enzyme-linked immunosorbent assays, immunoblot analysis, and quantitative reverse transcription polymerase chain reaction (RT-PCR). Cachexia-associated lipolysis was induced <i>in vitro</i> by stimulating differentiated adipocytes with recombinant LIF or interleukin (IL)-6 in the absence or presence of lipase or JAK inhibitors. These adipocytes were processed for glycerol release into the media, immunoblot analysis, and RT-PCR.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Tumour-secreted LIF induced changes in adipose tissue expression and serum levels of IL-6 and leptin in a JAK-dependent manner influencing cachexia-associated adipose wasting and anorexia. We identified two JAK inhibitors that block IL-6 family-mediated adipocyte lipolysis and IL-6 induction using an <i>in vitro</i> cachexia lipolysis assay. JAK inhibitors administered to the <i>in vivo</i> C26c20 cancer cachexia mouse models led to (i) a decrease in signal transducer and activator of transcription 3 phosphorylation in hypothalamic and adipose tissues, (ii) a reverse in the cachexia serum cytokine/adipokine signature, (iii) a delay in cancer cachexia-associated anorexia and adipose loss, and (iv) an improvement in overall survival.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>JAK inhibitors suppress LIF-associated adipose loss and anorexia in both <i>in vitro</i> and <i>in vivo</i> models of cancer cachexia.</p>\u0000 </section>\u0000 </div>","PeriodicalId":73544,"journal":{"name":"JCSM rapid communications","volume":"3 2","pages":"115-128"},"PeriodicalIF":0.0,"publicationDate":"2020-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/rco2.24","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71978550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sarcopenia is associated with poor prognosis in patients with chronic liver disease (CLD). As rapid skeletal muscle wasting predicts worse prognosis and a novel therapy for sarcopenia needs to be evaluated for validation, accurate evaluation methods for relative changes in muscle mass are crucial.
Methods
We screened CLD patients who had skeletal muscle mass evaluation between June 2015 and December 2017. Patients were included if they had adequate information, were followed for >6 months, and had skeletal muscle mass evaluation by both bioelectrical impedance analysis (BIA) and computed tomography (CT) imaging at baseline and the second evaluation point. We compared BIA and CT imaging in terms of their ability to quantify skeletal muscle mass and identify relative changes in muscle mass in CLD patients.
Results
Of the screened 447 CLD patients, 110 were included in this study, and 71 (64.5%) were men. The median age was 68 (range 21 to 90) years. In total, 83 (75.5%) and 32 (29.1%) patients had liver cirrhosis and hepatocellular carcinoma, respectively. Of them, 50 (45.5%) patients were liver cirrhosis patients without hepatocellular carcinoma through the observation period. Skeletal muscle mass index (SMI) by BIA, psoas muscle mass index (PMI), and SMI based on CT imaging were significantly correlated at baseline [SMI by simple CT method and SMI by BIA (r = 0.61, P < 0.01), SMI by BIA and PMI (r = 0.65, P < 0.01), and SMI by simple CT method and PMI (r = 0.82, P < 0.01), respectively] and second evaluation point [SMI by simple CT method and SMI by BIA (r = 0.51, P < 0.01), SMI by BIA and PMI (r = 0.58, P < 0.01), and SMI by simple CT method and PMI (r = 0.92, P < 0.01), respectively]. Similar to previous reports, based on the PMI and SMI by simple CT method, patients with more severe liver dysfunction experienced more rapid skeletal muscle mass loss (ΔSimple method/years and ΔPMI/years in patients with Child‑Pugh Classes A, B, and C: Child‑Pugh A, −3.34%; B, −11.77%; C, −18.78%; and Child‑Pugh A, −0.78%; B, −6.33%; C, −7.71%, respectively). Completely opposite results were obtained based on SMI by BIA (Child‑Pugh A, −0.70%; B, 1.42%; C, 12.48%). A subgroup analysis revealed that in patients with fluid retention and diuretic administration, SMI by BIA increased with time (P < 0.01).
{"title":"Computed tomography, not bioelectrical impedance analysis, is the proper method for evaluating changes in skeletal muscle mass in liver disease","authors":"Masatsugu Ohara, Goki Suda, Megumi Kimura, Osamu Maehara, Tomoe Shimazaki, Taku Shigesawa, Kazuharu Suzuki, Akihisa Nakamura, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Naoya Sakamoto","doi":"10.1002/rco2.20","DOIUrl":"10.1002/rco2.20","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Sarcopenia is associated with poor prognosis in patients with chronic liver disease (CLD). As rapid skeletal muscle wasting predicts worse prognosis and a novel therapy for sarcopenia needs to be evaluated for validation, accurate evaluation methods for relative changes in muscle mass are crucial.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We screened CLD patients who had skeletal muscle mass evaluation between June 2015 and December 2017. Patients were included if they had adequate information, were followed for >6 months, and had skeletal muscle mass evaluation by both bioelectrical impedance analysis (BIA) and computed tomography (CT) imaging at baseline and the second evaluation point. We compared BIA and CT imaging in terms of their ability to quantify skeletal muscle mass and identify relative changes in muscle mass in CLD patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Of the screened 447 CLD patients, 110 were included in this study, and 71 (64.5%) were men. The median age was 68 (range 21 to 90) years. In total, 83 (75.5%) and 32 (29.1%) patients had liver cirrhosis and hepatocellular carcinoma, respectively. Of them, 50 (45.5%) patients were liver cirrhosis patients without hepatocellular carcinoma through the observation period. Skeletal muscle mass index (SMI) by BIA, psoas muscle mass index (PMI), and SMI based on CT imaging were significantly correlated at baseline [SMI by simple CT method and SMI by BIA (<i>r</i> = 0.61, <i>P</i> < 0.01), SMI by BIA and PMI (<i>r</i> = 0.65, <i>P</i> < 0.01), and SMI by simple CT method and PMI (<i>r</i> = 0.82, <i>P</i> < 0.01), respectively] and second evaluation point [SMI by simple CT method and SMI by BIA (<i>r</i> = 0.51, <i>P</i> < 0.01), SMI by BIA and PMI (<i>r</i> = 0.58, <i>P</i> < 0.01), and SMI by simple CT method and PMI (<i>r</i> = 0.92, <i>P</i> < 0.01), respectively]. Similar to previous reports, based on the PMI and SMI by simple CT method, patients with more severe liver dysfunction experienced more rapid skeletal muscle mass loss (ΔSimple method/years and ΔPMI/years in patients with Child‑Pugh Classes A, B, and C: Child‑Pugh A, −3.34%; B, −11.77%; C, −18.78%; and Child‑Pugh A, −0.78%; B, −6.33%; C, −7.71%, respectively). Completely opposite results were obtained based on SMI by BIA (Child‑Pugh A, −0.70%; B, 1.42%; C, 12.48%). A subgroup analysis revealed that in patients with fluid retention and diuretic administration, SMI by BIA increased with time (<i>P</i> < 0.01).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 ","PeriodicalId":73544,"journal":{"name":"JCSM rapid communications","volume":"3 2","pages":"103-114"},"PeriodicalIF":0.0,"publicationDate":"2020-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/rco2.20","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47167239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Erin S. Sullivan, Louise E. Daly, Derek G. Power, Aoife M. Ryan
Background
Weight loss (WL) and sarcopenia are associated with negative oncological outcomes including poor treatment tolerance, decreased quality of life, and reduced survival. The number of patients affected by sarcopenia and WL in Ireland and the UK is unknown.
Methods
A systematic review was undertaken to determine median rate of WL > 5% and computed tomography-diagnosed sarcopenia in oncology populations. Gaps in the literature were supplemented using local data, collected as part of a 5 year prospective study. Rates of WL and sarcopenia in the population were extrapolated from these data based on incidence and prevalence of each cancer as per national cancer registries.
Results
We estimated that across Ireland and the UK, 128 892 cancer patients (34%) are affected by WL > 5% annually (121 641 UK; 7251 Ireland) and there are 133 707 annual cases of sarcopenia in cancer patients (35%) (126 265 UK; 7442 Ireland). Furthermore, we estimate that there are 716 124 and 771 589 cancer survivors with history of WL > 5% or sarcopenia, respectively.
Conclusions
Large numbers of patients are affected by cancer-related malnutrition. Given the impact of malnutrition on oncological outcomes and long-term frailty, there is an urgent need to improve access to cancer nutrition care.
{"title":"Epidemiology of cancer-related weight loss and sarcopenia in the UK and Ireland: incidence, prevalence, and clinical impact","authors":"Erin S. Sullivan, Louise E. Daly, Derek G. Power, Aoife M. Ryan","doi":"10.1002/rco2.19","DOIUrl":"10.1002/rco2.19","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Weight loss (WL) and sarcopenia are associated with negative oncological outcomes including poor treatment tolerance, decreased quality of life, and reduced survival. The number of patients affected by sarcopenia and WL in Ireland and the UK is unknown.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A systematic review was undertaken to determine median rate of WL > 5% and computed tomography-diagnosed sarcopenia in oncology populations. Gaps in the literature were supplemented using local data, collected as part of a 5 year prospective study. Rates of WL and sarcopenia in the population were extrapolated from these data based on incidence and prevalence of each cancer as per national cancer registries.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We estimated that across Ireland and the UK, 128 892 cancer patients (34%) are affected by WL > 5% annually (121 641 UK; 7251 Ireland) and there are 133 707 annual cases of sarcopenia in cancer patients (35%) (126 265 UK; 7442 Ireland). Furthermore, we estimate that there are 716 124 and 771 589 cancer survivors with history of WL > 5% or sarcopenia, respectively.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Large numbers of patients are affected by cancer-related malnutrition. Given the impact of malnutrition on oncological outcomes and long-term frailty, there is an urgent need to improve access to cancer nutrition care.</p>\u0000 </section>\u0000 </div>","PeriodicalId":73544,"journal":{"name":"JCSM rapid communications","volume":"3 2","pages":"91-102"},"PeriodicalIF":0.0,"publicationDate":"2020-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/rco2.19","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48573176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ravneet Vohra, Matthew D. Campbell, Joshua Park, Stella Whang, Kayla Gravelle, Yak-Nam Wang, Joo-Ha Hwang, David J. Marcinek, Donghoon Lee
Background
Cancer cachexia is a multifactorial wasting syndrome that is characterized by the loss of skeletal muscle mass and weakness, which compromises physical function, reduces quality of life, and ultimately can lead to mortality. Experimental models of cancer cachexia have recapitulated this skeletal muscle atrophy and consequent decline in muscle force-generating capacity. We address these issues in a novel transgenic mouse model Kras, Trp53, and Pdx-1-Cre (KPC) of pancreatic ductal adenocarcinoma using multi-parametric magnetic resonance measures.
Methods
KPC mice (n = 10) were divided equally into two groups (n = 5 per group) depending on the size of the tumour, that is, tumour size <250 and >250 mm3. Using multi-parametric magnetic resonance measures, we demonstrated the changes in the gastrocnemius muscle at the microstructural level. In addition, we evaluated skeletal muscle contractile function in KPC mice using an in vivo approach.
Results
Increase in tumour size resulted in decrease in gastrocnemius maximum cross-sectional area, decrease in T2 relaxation time, increase in magnetization transfer ratio, decrease in mean diffusivity, and decrease in radial diffusivity of water across the muscle fibres. Finally, we detected significant decrease in absolute and specific force production of gastrocnemius muscle with increase in tumour size.
Conclusions
Our findings indicate that increase in tumour size may cause alterations in structural and functional parameters of skeletal muscles and that MR parameters may be used as sensitive biomarkers to non-invasively detect structural changes in cachectic muscles.
{"title":"Increased tumour burden alters skeletal muscle properties in the KPC mouse model of pancreatic cancer","authors":"Ravneet Vohra, Matthew D. Campbell, Joshua Park, Stella Whang, Kayla Gravelle, Yak-Nam Wang, Joo-Ha Hwang, David J. Marcinek, Donghoon Lee","doi":"10.1002/rco2.13","DOIUrl":"10.1002/rco2.13","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Cancer cachexia is a multifactorial wasting syndrome that is characterized by the loss of skeletal muscle mass and weakness, which compromises physical function, reduces quality of life, and ultimately can lead to mortality. Experimental models of cancer cachexia have recapitulated this skeletal muscle atrophy and consequent decline in muscle force-generating capacity. We address these issues in a novel transgenic mouse model Kras, Trp53, and Pdx-1-Cre (<i>KPC</i>) of pancreatic ductal adenocarcinoma using multi-parametric magnetic resonance measures.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p><i>KPC</i> mice (<i>n</i> = 10) were divided equally into two groups (<i>n</i> = 5 per group) depending on the size of the tumour, that is, tumour size <250 and >250 mm<sup>3</sup>. Using multi-parametric magnetic resonance measures, we demonstrated the changes in the gastrocnemius muscle at the microstructural level. In addition, we evaluated skeletal muscle contractile function in <i>KPC</i> mice using an <i>in vivo</i> approach.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Increase in tumour size resulted in decrease in gastrocnemius maximum cross-sectional area, decrease in T<sub>2</sub> relaxation time, increase in magnetization transfer ratio, decrease in mean diffusivity, and decrease in radial diffusivity of water across the muscle fibres. Finally, we detected significant decrease in absolute and specific force production of gastrocnemius muscle with increase in tumour size.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings indicate that increase in tumour size may cause alterations in structural and functional parameters of skeletal muscles and that MR parameters may be used as sensitive biomarkers to non-invasively detect structural changes in cachectic muscles.</p>\u0000 </section>\u0000 </div>","PeriodicalId":73544,"journal":{"name":"JCSM rapid communications","volume":"3 2","pages":"44-55"},"PeriodicalIF":0.0,"publicationDate":"2020-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/rco2.13","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38502653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lara Zwakman-Hessels, Miriam Zeillemaker-Hoekstra, Maarten W. Nijsten
Background
Cachexia complicates many chronic diseases. In chronic or congestive heart failure (CHF), cachexia independently contributes to decreased survival. Although diuretics have long been part of standard treatment of CHF, the addition of angiotensin and aldosterone antagonists to the standard treatment regimen has considerably improved the outcome of CHF. Both loop diuretics and the up-regulation of the renin–angiotensin–aldosterone system caused by CHF induce loss of total body potassium (TBK).
Hypothesis
In addition to the causal association of loss of muscle mass with loss of TBK, we propose that the reverse mechanism also exists. The known beneficial effects of angiotensin and aldosterone inhibition may partly result from preserved TBK with consequent muscle mass preservation.
Conclusion
We propose that monitoring of muscle mass, potassium balances, and TBK should be included in future CHF studies to verify this hypothesis and allow further optimization of therapy.
{"title":"Hypothesis: Potassium sparing by angiotensin and aldosterone inhibitors preserves skeletal muscle mass in chronic heart failure","authors":"Lara Zwakman-Hessels, Miriam Zeillemaker-Hoekstra, Maarten W. Nijsten","doi":"10.1002/rco2.17","DOIUrl":"10.1002/rco2.17","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Cachexia complicates many chronic diseases. In chronic or congestive heart failure (CHF), cachexia independently contributes to decreased survival. Although diuretics have long been part of standard treatment of CHF, the addition of angiotensin and aldosterone antagonists to the standard treatment regimen has considerably improved the outcome of CHF. Both loop diuretics and the up-regulation of the renin–angiotensin–aldosterone system caused by CHF induce loss of total body potassium (TBK).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Hypothesis</h3>\u0000 \u0000 <p>In addition to the causal association of loss of muscle mass with loss of TBK, we propose that the reverse mechanism also exists. The known beneficial effects of angiotensin and aldosterone inhibition may partly result from preserved TBK with consequent muscle mass preservation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We propose that monitoring of muscle mass, potassium balances, and TBK should be included in future CHF studies to verify this hypothesis and allow further optimization of therapy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":73544,"journal":{"name":"JCSM rapid communications","volume":"3 2","pages":"77-80"},"PeriodicalIF":0.0,"publicationDate":"2020-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/rco2.17","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42787128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Paige C. Arneson-Wissink, Kelly A. Hogan, Alexandra M. Ducharme, Adrienne Samani, Aminah Jatoi, Jason D. Doles
Background
Muscle wasting is a debilitating co-morbidity affecting most advanced cancer patients. Alongside enhanced muscle catabolism, defects in muscle repair/regeneration contribute to cancer-associated wasting. Among the factors implicated in suppression of muscle regeneration are cytokines that interfere with myogenic signal transduction pathways. Less understood is how other cancer/wasting-associated cues, such as metabolites, contribute to muscle dysfunction. This study investigates how the metabolite succinate affects myogenesis and muscle regeneration.
Methods
We leveraged an established ectopic metabolite treatment (cell permeable dimethyl-succinate) strategy to evaluate the ability of intracellular succinate elevation to (i) affect myoblast homeostasis (proliferation and apoptosis), (ii) disrupt protein dynamics and induce wasting-associated atrophy, and (iii) modulate in vitro myogenesis. In vivo succinate supplementation experiments (2% succinate and 1% sucrose vehicle) were used to corroborate and extend in vitro observations. Metabolic profiling and functional metabolic studies were then performed to investigate the impact of succinate elevation on mitochondria function.
Results
We found that in vitro succinate supplementation elevated intracellular succinate about 2-fold and did not have an impact on proliferation or apoptosis of C2C12 myoblasts. Elevated succinate had minor effects on protein homeostasis (~25% decrease in protein synthesis assessed by O-propargyl-puromycin staining), and no significant effect on myotube atrophy. Succinate elevation interfered with in vitro myoblast differentiation, characterized by significant decreases in late markers of myogenesis and fewer nuclei per myosin heavy chain positive structure (assessed by immunofluorescence staining). While mice orally administered succinate did not exhibit changes in overall body composition or whole muscle weights, these mice displayed smaller muscle myofiber diameters (~6% decrease in the mean of non-linear regression curves fit to the histograms of minimum feret diameter distribution), which was exacerbated when muscle regeneration was induced with barium chloride injury. Significant decreases in the mean of non-linear regression curves fit to the histograms of minimum feret diameter distributions were observed 7 and 28 days post injury. Elevated numbers of myogenin positive cells (three-fold increase) supportive of the differentiation defects observed in vitro were observed 28 days post injury. Metabolic profiling and
{"title":"The wasting-associated metabolite succinate disrupts myogenesis and impairs skeletal muscle regeneration","authors":"Paige C. Arneson-Wissink, Kelly A. Hogan, Alexandra M. Ducharme, Adrienne Samani, Aminah Jatoi, Jason D. Doles","doi":"10.1002/rco2.14","DOIUrl":"10.1002/rco2.14","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Muscle wasting is a debilitating co-morbidity affecting most advanced cancer patients. Alongside enhanced muscle catabolism, defects in muscle repair/regeneration contribute to cancer-associated wasting. Among the factors implicated in suppression of muscle regeneration are cytokines that interfere with myogenic signal transduction pathways. Less understood is how other cancer/wasting-associated cues, such as metabolites, contribute to muscle dysfunction. This study investigates how the metabolite succinate affects myogenesis and muscle regeneration.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We leveraged an established ectopic metabolite treatment (cell permeable dimethyl-succinate) strategy to evaluate the ability of intracellular succinate elevation to (i) affect myoblast homeostasis (proliferation and apoptosis), (ii) disrupt protein dynamics and induce wasting-associated atrophy, and (iii) modulate <i>in vitro</i> myogenesis. <i>In vivo</i> succinate supplementation experiments (2% succinate and 1% sucrose vehicle) were used to corroborate and extend <i>in vitro</i> observations. Metabolic profiling and functional metabolic studies were then performed to investigate the impact of succinate elevation on mitochondria function.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found that <i>in vitro</i> succinate supplementation elevated intracellular succinate about 2-fold and did not have an impact on proliferation or apoptosis of C2C12 myoblasts. Elevated succinate had minor effects on protein homeostasis (~25% decrease in protein synthesis assessed by O-propargyl-puromycin staining), and no significant effect on myotube atrophy. Succinate elevation interfered with <i>in vitro</i> myoblast differentiation, characterized by significant decreases in late markers of myogenesis and fewer nuclei per myosin heavy chain positive structure (assessed by immunofluorescence staining). While mice orally administered succinate did not exhibit changes in overall body composition or whole muscle weights, these mice displayed smaller muscle myofiber diameters (~6% decrease in the mean of non-linear regression curves fit to the histograms of minimum feret diameter distribution), which was exacerbated when muscle regeneration was induced with barium chloride injury. Significant decreases in the mean of non-linear regression curves fit to the histograms of minimum feret diameter distributions were observed 7 and 28 days post injury. Elevated numbers of myogenin positive cells (three-fold increase) supportive of the differentiation defects observed <i>in vitro</i> were observed 28 days post injury. Metabolic profiling and","PeriodicalId":73544,"journal":{"name":"JCSM rapid communications","volume":"3 2","pages":"56-69"},"PeriodicalIF":0.0,"publicationDate":"2020-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/rco2.14","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38359622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tábata L. Nascimento, Ruben Mestril, Elen H. Miyabara
Background
The aim of the present investigation is to evaluate the effect of the overexpression of inducible 70-kDa heat shock protein (HSP70) on sarcopenic muscles of aged mice.
Methods
Tibialis anterior muscles of aged and young transgenic mice overexpressing HSP70 and wild-type mice were evaluated. Old mice were treated with the HSP inducer O-[3-piperidino-2-hydroxy-1-propyl]-nicotinic amidoxime (BGP-15) for 10 days, and their muscles were analysed.
Results
Old HSP70 transgenic mice presented a less pronounced decrease in myofiber size, lower protein levels of Foxo3a, and a spared increase in miRNA-133b expression when compared with old wild-type mice. Moreover, in BGP-15-treated old mice, the reduction in myofiber size was less intense, and the decline in muscle specific force was attenuated.
Conclusions
These results suggest that HSP70 overexpression attenuates sarcopenia in old mice, and this effect may be mediated by miR-133b down-regulation. In addition, BGP-15 treatment may be a useful strategy to mitigate the effects of sarcopenia in old mice.
本研究的目的是评估诱导型70‐kDa热休克蛋白(HSP70)过表达对老年小鼠肌肉减少症的影响。
{"title":"Overexpression of HSP70 attenuates sarcopenia by suppressing the expression of miR-133b","authors":"Tábata L. Nascimento, Ruben Mestril, Elen H. Miyabara","doi":"10.1002/rco2.12","DOIUrl":"10.1002/rco2.12","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The aim of the present investigation is to evaluate the effect of the overexpression of inducible 70-kDa heat shock protein (HSP70) on sarcopenic muscles of aged mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Tibialis anterior muscles of aged and young transgenic mice overexpressing HSP70 and wild-type mice were evaluated. Old mice were treated with the HSP inducer O-[3-piperidino-2-hydroxy-1-propyl]-nicotinic amidoxime (BGP-15) for 10 days, and their muscles were analysed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Old HSP70 transgenic mice presented a less pronounced decrease in myofiber size, lower protein levels of Foxo3a, and a spared increase in miRNA-133b expression when compared with old wild-type mice. Moreover, in BGP-15-treated old mice, the reduction in myofiber size was less intense, and the decline in muscle specific force was attenuated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These results suggest that HSP70 overexpression attenuates sarcopenia in old mice, and this effect may be mediated by miR-133b down-regulation. In addition, BGP-15 treatment may be a useful strategy to mitigate the effects of sarcopenia in old mice.</p>\u0000 </section>\u0000 </div>","PeriodicalId":73544,"journal":{"name":"JCSM rapid communications","volume":"3 2","pages":"70-76"},"PeriodicalIF":0.0,"publicationDate":"2020-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/rco2.12","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43336800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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