Article first published online: 11 October 2018
Stephan von Haehling, Markus S. Anker, Nicole Ebner, Stefan D. Anker
von Haehling, S., Anker, M. S., Ebner, N., and Anker, S. D. (2018) Time to jump on the bandwagon: the Journal of Cachexia, Sarcopenia and Muscle in 2018. Journal of Cachexia, Sarcopenia and Muscle, 9: 793–801. https://doi.org/10.1002/jcsm.12356.
Article first published online: 4 September 2018
Magdalena Dziegala, Krystian Josiak, Monika Kasztura, Kamil Kobak, Stephan von Haehling, Waldemar Banasiak, Stefan D. Anker, Piotr Ponikowski, Ewa Jankowska
Iron deficiency as energetic insult to skeletal muscle in chronic diseases
Specific skeletal myopathy constitutes a common feature of heart failure, chronic obstructive pulmonary disease, and type 2 diabetes mellitus, where it can be characterized by the loss of skeletal muscle oxidative capacity. There is evidence from in vitro and animal studies that iron deficiency affects skeletal muscle functioning mainly in the context of its energetics by limiting oxidative metabolism in favour of glycolysis and by alterations in both carbohydrate and fat catabolic processing. In this review, we depict the possible molecular pathomechanisms of skeletal muscle energetic impairment and postulate iron deficiency as an important factor causally linked to loss of muscle oxidative capacity that contributes to skeletal myopathy seen in patients with heart failure, chronic obstructive pulmonary disease, and type 2 diabetes mellitus.
Dziegala, M., Josiak, K., Kasztura, M., Kobak, K., von Haehling, S., Banasiak, W., Anker, S. D., Ponikowski, P., and Jankowska, E. (2018) Iron deficiency as energetic insult to skeletal muscle in chronic diseases. Journal of Cachexia, Sarcopenia and Muscle, 9: 802–815. https://doi.org/10.1002/jcsm.12314.
Article first published online: 21 August 2018
Rafaela C.E. Santo, Kevin Z. Fernandes, Priscila S. Lora, Lidiane I. Filippin, Ricardo M. Xavier
Prevalence of rheumatoid cachexia in rheumatoid arthritis: a systematic review and meta‐analysis
Low muscle mass occurs in patients with rheumatoid arthritis without weight loss; this condition is referred as rheumatoid cachexia. The aim of the current study was to perform a systematic review with meta‐analysis to determine the rheumatoid cachexia prevalence.
A systematic review with meta‐analysis of observational studies published in English, between 1994 and 2016, was conducted using MEDLINE (via PubMed) and other relevant sources. Search strategies were based on pre‐defined keywords and medical subject headings. The methodological quality of included studies was assessed using the Newcastle‐Ottawa Scale. Meta‐analysis was used to estimate the prevalence, and because studies reported different methods and criteria to estimate body composition and prevalence of rheumatoid cachexia, subgroup analyses were performed. Meta‐regression adjusted for the 28‐joint disease activity score and disease duration (years) was performed (significance level at P ≤ 0.05).
Of 136 full articles (one duplicate publication) screened for inclusion in the study, eight were included. The estimated overall prevalence of rheumatoid cachexia was 19% [95% confidence interval (CI) 07–33%]. This prevalence was 29% (95% CI 15–46%) when body composition was measured by dual‐energy X‐ray absorptiometry. When the diagnostic criteria were fat‐free mass index below the 10th percentile and fat mass index above the 25th percentile, rheumatoid cachexia prevalence was 32% (95% CI 14–52%). The 28‐joint disease activity score and disease duration had no influence on the estimated prevalence of rheumatoid cachexia (P > 0.05). Most studies were rated as having moderate methodological quality.
Meta‐analysis showed a prevalence of rheumatoid cachexia of 15‐32%, according to different criteria, demonstrating that this condition is a frequent comorbidity of rheumatoid arthritis. To better understand its clinical impact, more studies using standardized definitions and prospective evaluations are urgently needed.
Santo, R. C. E., Fernandes, K. Z., Lora, P. S., Filippin, L. I., and Xavier, R. M. (2018) Prevalence of rheumatoid cachexia in rheumatoid arthritis: a systematic review and meta‐analysis. Journal of Cachexia, Sarcopenia and Muscle, 9: 816–825. https://doi.org/10.1002/jcsm.12320.
Article first published online: 26 September 2018
Sophia Z. Liu, Amir S. Ali, Matthew D. Campbell, Kevin Kilroy, Eric G. Shankland, Baback Roshanravan, David J. Marcinek, Kevin E. Conley
Building strength, endurance, and mobility using an astaxanthin formulation with functional training in elderly
Building both strength and endurance has been a challenge in exercise training in the elderly, but dietary supplements hold promise as agents for improving muscle adaptation. Here, we test a formulation of natural products (AX: astaxanthin, 12 mg and tocotrienol, 10 mg and zinc, 6 mg) with both anti-inflammatory and antioxidant properties in combination with exercise. We conducted a randomized, double-blind, placebo-controlled study of elderly subjects (65–82 years) on a daily oral dose with interval walking exercise on an incline treadmill.
Forty-two subjects were fed AX or placebo for 4 months and trained 3 months (3×/week for 40–60 min) with increasing intervals of incline walking. Strength was measured as maximal voluntary force (MVC) in ankle dorsiflexion exercise, and tibialis anterior muscle size (cross-sectional area, CSA) was determined from magnetic resonance imaging.
Greater endurance (exercise time in incline walking, >50%) and distance in 6 min walk (>8%) accompanied training in both treatments. Increases in MVC by 14.4% (±6.2%, mean ± SEM, P < 0.02, paired t-test), CSA by 2.7% (±1.0%, P < 0.01), and specific force by 11.6% (MVC/CSA, ±6.0%, P = 0.05) were found with AX treatment, but no change was evident in these properties with placebo treatment (MVC, 2.9% ± 5.6%; CSA, 0.6% ± 1.2%; MVC/CSA, 2.4 ± 5.7%; P > 0.6 for all).
The AX formulation improved muscle strength and CSA in healthy elderly in addition to the elevation in endurance and walking distance found with exercise training alone. Thus, the AX formulation in combination with a functional training programme uniquely improved muscle strength, endurance, and mobility in the elderly.
Liu, S. Z., Ali, A. S., Campbell, M. D., Kilroy, K., Shankland, E. G., Roshanravan, B., Marcinek, D. J., and Conley, K. E. (2018) Building strength, endurance, and mobility using an astaxanthin formulation with functional training in elderly. Journal of Cachexia, Sarcopenia and Muscle, 9: 826–833. https://doi.org/10.1002/jcsm.12318.
Article first published online: 14 August 2018
Kota Tsutsumimoto,Takehiko Doi, Hyuma Makizako, Ryo Hotta, Sho Nakakubo, Keitaro Makino, Takao Suzuki, Hiroyuki Shimada
Aging‐related anorexia and its association with disability and frailty
Anorexia of ageing may be a precursor to various geriatric syndromes. We elucidated whether anorexia of ageing had a significant impact on incident disability and investigated whether anorexia of ageing had a direct association with future disability or an indirect association with disability via frailty.
This study employed an observational, longitudinal, cohort design in a community setting. Participants were 4393 older adults (75.9 ± 4.3 years). Anorexia of ageing was assessed by a simplified nutritional appetite questionnaire. Frailty was operationalized as slowness, weakness, exhaustion, low physical activity, and weight loss. Participants who had none of these characteristics were considered robust, those with one or two characteristics were considered pre‐frail, and those with three or more characteristics were considered frail. We examined sociodemographic variables (age, sex, and education), medical history (medication and chronic disease history), lifestyle factors (smoking and drinking habits and living arrangement), body mass index, blood nutrition data, depressive symptoms, physical functioning, and cognitive functioning.
The prevalence of anorexia of ageing was 10.7% (n = 468). The proportion of physical frailty, pre‐frailty, and robustness were 8.4, 52.0, and 39.6%, respectively, in the without anorexia of ageing group, and 20.3, 57.7, and 22.0%, respectively, in the anorexia of ageing group (P < 0.001). During a 2‐year follow‐up, the prevalence proportion of disability was 5.6% in the without anorexia of ageing group and 10.7% in the anorexia of ageing group (P < 0.001). Adjusted for covariates (except for frailty status), the participants with anorexia of ageing had an independently associated higher risk of incident disability compared with those without anorexia of ageing (hazard ratio: 1.43, 95% confidence interval: 1.04–1.95, P = 0.03). However, adjusted for covariates (including frailty status), anorexia of ageing was not significantly associated with incident disability (P = 0.09). Structural equation models revealed that anorexia of ageing had no direct effect on disability; however, anorexia of ageing was associated with frailty.
Older adults with anorexia of ageing had a higher proportion of frailty and a higher prevalence proportion of disability compared with those without anorexia of ageing. Although anorexia of ageing may not have a direct effect on incident disability, the structural equation model suggests an indirect relationship between anorexia of ageing and incident disability via frailty status.
Tsutsumimoto, K., Doi, T., Makizako, H., Hotta, R., Nakakubo, S., Makino, K., Suzuki, T., and Shimada, H. (2018) Aging‐related anorexia and its association with disability and frailty. Journal of Cachexia, Sarcopenia and Muscle, 9: 834–843. https://doi.org/10.1002/jcsm.12330.
Article first published online: 30 August 2018
Masaya Tsuda, Arata Fukushima, Junichi Matsumoto, Shingo Takada, Naoya Kakutani, Hideo Nambu, Katsuma Yamanashi, Takaaki Furihata, Takashi Yokota, Koichi Okita, Shintaro Kinugawa, Toshihisa Anzai
Protein acetylation in skeletal muscle mitochondria is involved in impaired fatty acid oxidation and exercise intolerance in heart failure
Exercise intolerance is a common clinical feature and is linked to poor prognosis in patients with heart failure (HF). Skeletal muscle dysfunction, including impaired energy metabolism in the skeletal muscle, is suspected to play a central role in this intolerance, but the underlying mechanisms remain elusive. Lysine acetylation, a recently identified post-translational modification, has emerged as a major contributor to the derangement of mitochondrial metabolism. We thus investigated whether mitochondrial protein acetylation is associated with impaired skeletal muscle metabolism and lowered exercise capacity in both basic and clinical settings of HF.
We first conducted a global metabolomic analysis to determine whether plasma acetyl-lysine is a determinant factor for peak oxygen uptake (peak VO2) in HF patients. We then created a murine model of HF (n = 11) or sham-operated (n = 11) mice with or without limited exercise capacity by ligating a coronary artery, and we tested the gastrocnemius tissues by using mass spectrometry-based acetylomics. A causative relationship between acetylation and the activity of a metabolic enzyme was confirmed in in vitro studies.
The metabolomic analysis verified that acetyl-lysine was the most relevant metabolite that was negatively correlated with peak VO2 (r = -0.81, P < 0.01). At 4 weeks post-myocardial infarction HF, a treadmill test showed lowered work (distance × body weight) and peak VO2 in the HF mice compared with the sham-operated mice (11 ± 1 vs. 23 ± 1 J, P < 0.01; 143 ± 5 vs. 159 ± 3 mL/kg/min, P = 0.01; respectively). As noted, the protein acetylation of gastrocnemius mitochondria was 48% greater in the HF mice than the sham-operated mice (P = 0.047). Acetylproteomics identified the mitochondrial enzymes involved in fatty acid ß-oxidation (FAO), the tricarboxylic acid cycle, and the electron transport chain as targets of acetylation. In parallel, the FAO enzyme (ß-hydroxyacyl CoA dehydrogenase) activity and fatty acid-driven mitochondrial respiration were reduced in the HF mice. This alteration was associated with a decreased expression of mitochondrial deacetylase, Sirtuin 3, because silencing of Sirtuin 3 in cultured skeletal muscle cells resulted in increased mitochondrial acetylation and reduced ß-hydroxyacyl CoA dehydrogenase activity.
Enhanced mitochondrial protein acetylation is associated with impaired FAO in skeletal muscle and reduced exercise capacity in HF. Our results indicate that lysine acetylation is a crucial mechanism underlying deranged skeletal muscle metabolism, suggesting that its modulation is a potential approach for exercise intolerance in HF.
Tsuda, M., Fukushima, A., Matsumoto, J., Takada, S., Kakutani, N., Nambu, H., Yamanashi, K., Furihata, T., Yokota, T., Okita, K., Kinugawa, S., and Anzai, T. (2018) Protein acetylation in skeletal muscle mitochondria is involved in impaired fatty acid oxidation and exercise intolerance in heart failure. Journal of Cachexia, Sarcopenia and Muscle, 9: 844–859. https://doi.org/10.1002/jcsm.12322.
Article first published online: 30 August 2018
Seong Hee Kang, Woo Kyoung Jeong, Soon Koo Baik, Seung Hwan Cha, Moon Young Kim
Impact of sarcopenia on prognostic value of cirrhosis: going beyond the hepatic venous pressure gradient and MELD scoreBackground
Sarcopenia has been reported as a prognostic factor. We evaluated the impact of sarcopenia to the conventional prognostic factors [Model for End‐Stage Liver Disease (MELD) score, Child–Turcotte–Pugh (CTP) score, hepatic venous pressure gradient (HVPG)] in cirrhosis.
Overall, 452 patients with cirrhosis were stratified by MELD score (low < 15, high ≥ 15), CTP class, and HVPG [non‐clinically significant portal hypertension (CSPH), 6–9 mmHg; CSPH, 10–19 mmHg; extremely severe PH, ≥20 mmHg]. L3 skeletal muscle index as marker of sarcopenia was subdivided into quartiles (47.01–52.25–58.22 cm2/m2).
Among the patients, 42% (190/452) presented with sarcopenia. During a median follow‐up period of 21.2 months, sarcopenia was associated with mortality (adjusted hazard ratio = 2.253, P < 0.001) and specifically with compensated and early decompensated stages of cirrhosis, but not with advanced decompensated stages; low (P < 0.001) and high (P = 0.095) MELD scores; CTP classes A (P = 0.034), B (P < 0.001), and C (P = 0.205); and non‐CSPH (P = 0.018), CSPH (P < 0.001), and extremely severe PH (P = 0.846). In quartiles of sarcopenia, MELD score, CTP class, and HVPG were independent predictors of mortality in non‐sarcopenia, but not in severe sarcopenia (MELD, P = 0.182; CTP, P = 0.187; HVPG, P = 0.077).
Sarcopenia is associated with mortality in compensated and early decompensated cirrhosis, and existing conventional prognostic factors had limited value in severe sarcopenia. Therefore, incorporating sarcopenia in the conventional prognostic factors had added value, particularly in compensated and early decompensated cirrhosis. Subclassification of prognostic factors according to sarcopenia may help to better assess the prognosis of cirrhosis.
Kang, S. H., Jeong, W. K., Baik, S. K., Cha, S. H., and Kim, M. Y. (2018) Impact of sarcopenia on prognostic value of cirrhosis: going beyond the hepatic venous pressure gradient and MELD score. Journal of Cachexia, Sarcopenia and Muscle, 9: 860–870. https://doi.org/10.1002/jcsm.12333.
Article first published online: 27 July 2018
Talia Golan, Ravit Geva, Donald Richards, Srinivasan Madhusudan, Boris Kin Lin, Haofei Tiffany Wang, Richard A. Walgren, Salomon M. Stemmer
LY2495655, an antimyostatin antibody, in pancreatic cancer: a randomized, phase 2 trial
Cachexia is a formidable clinical challenge in pancreatic cancer. We assessed LY2495655 (antimyostatin antibody) plus standard-of-care chemotherapy in pancreatic cancer using cachexia status as a stratifier.
In this randomized, phase 2 trial, patients with stage II–IV pancreatic cancer were randomized to 300 mg LY2495655, 100 mg LY2495655, or placebo, plus physician-choice chemotherapy from a prespecified list of standard-of-care regimens for first and later lines of care. Investigational treatment was continued during second-line treatment. The primary endpoint was overall survival.
Overall, 125 patients were randomized. In August 2014, 300 mg LY2495655 was terminated due to imbalance in death rates between the treatment arms; in January 2015, 100 mg LY2495655 treatment was terminated due to futility. LY2495655 did not improve overall survival: the hazard ratio was 1.70 (90% confidence interval, 1.1–2.7) for 300 mg vs. placebo and 1.3 (0.82–2.1) for 100 mg vs. placebo (recommended doses). Progression-free survival results were consistent with the overall survival results. A numerically higher hazard ratio was observed in patients with weight loss (WL) of =5% (cachexia) than with <5% WL within 6 months before randomization. Subgroup analyses for patients stratified by WL in the 6 months preceding enrollment suggested that functional responses to LY2495655 (either dose) may have been superior in patients with <5% WL vs. patients with =5% WL. Among possibly drug-related adverse events, fatigue, diarrhoea, and anorexia were more common in LY2495655-treated than in placebo-treated patients.
In the intention-to-treat analysis, LY2495655 did not confer clinical benefit in pancreatic cancer. Our data highlight the importance of assessing survival when investigating therapeutic management of cachexia and support the use of WL as a stratifier (independent of performance status).
Golan, T., Geva, R., Richards, D., Madhusudan, S., Lin, B. K., Wang, H. T., Walgren, R. A., and Stemmer, S. M. (2018) LY2495655, an antimyostatin antibody, in pancreatic cancer: a randomized, phase 2 trial. Journal of Cachexia, Sarcopenia and Muscle, 9: 871–879. https://doi.org/10.1002/jcsm.12331.
Article first published online: 19 September 2018
Tobias Winkler, Carsten Perka, Philipp von Roth, Alison N. Agres, Henning Plage, Bernd Preininger, Matthias Pumberger, Sven Geissler, Esther Lukasiewicz Hagai, Racheli Ofir, Lena Pinzur, Eli Eyal, Gisela Stoltenburg-Didinger, Christian Meisel, Christine Consentius, Mathias Streitz, Petra Reinke, Georg N. Duda, Hans-Dieter Volk
Immunomodulatory placental-expanded, mesenchymal stromal cells improve muscle function following hip arthroplasty
No regenerative approach has thus far been shown to be effective in skeletal muscle injuries, despite their high frequency and associated functional deficits. We sought to address surgical trauma-related muscle injuries using local intraoperative application of allogeneic placenta-derived, mesenchymal-like adherent cells (PLX-PAD), using hip arthroplasty as a standardized injury model, because of the high regenerative and immunomodulatory potency of this cell type.
Our pilot phase I/IIa study was prospective, randomized, double blind, and placebo-controlled. Twenty patients undergoing hip arthroplasty via a direct lateral approach received an injection of 3.0 × 108 (300 M, n = 6) or 1.5 × 108 (150 M, n = 7) PLX-PAD or a placebo (n = 7) into the injured gluteus medius muscles.
We did not observe any relevant PLX-PAD-related adverse events at the 2-year follow-up. Improved gluteus medius strength was noted as early as Week 6 in the treatment-groups. Surprisingly, until Week 26, the low-dose group outperformed the high-dose group and reached significantly improved strength compared with placebo [150 M vs. placebo: P = 0.007 (baseline adjusted; 95% confidence interval 7.6, 43.9); preoperative baseline values mean ± SE: placebo: 24.4 ± 6.7 Nm, 150 M: 27.3 ± 5.6 Nm], mirrored by an increase in muscle volume [150 M vs. placebo: P = 0.004 (baseline adjusted; 95% confidence interval 6.0, 30.0); preoperative baseline values GM volume: placebo: 211.9 ± 15.3 cm3, 150 M: 237.4 ± 27.2 cm3]. Histology indicated accelerated healing after cell therapy. Biomarker studies revealed that low-dose treatment reduced the surgery-related immunological stress reaction more than high-dose treatment (exemplarily: CD16+ NK cells: Day 1 P = 0.06 vs. placebo, P = 0.07 vs. 150 M; CD4+ T-cells: Day 1 P = 0.04 vs. placebo, P = 0.08 vs. 150 M). Signs of late-onset immune reactivity after high-dose treatment corresponded to reduced functional improvement.
Allogeneic PLX-PAD therapy improved strength and volume of injured skeletal muscle with a reasonable safety profile. Outcomes could be positively correlated with the modulation of early postoperative stress-related immunological reactions.
Winkler, T., Perka, C., von Roth, P., Agres, A. N., Plage, H., Preininger, B., Pumberger, M., Geissler, S., Hagai, E. L., Ofir, R., Pinzur, L., Eyal, E., Stoltenburg‐Didinger, G., Meisel, C., Consentius, C., Streitz, M., Reinke, P., Duda, G. N., and Volk, H.‐D. (2018) Immunomodulatory placental‐expanded, mesenchymal stromal cells improve muscle function following hip arthroplasty. Journal of Cachexia, Sarcopenia and Muscle, 9: 880–897. https://doi.org/10.1002/jcsm.12316.
Article first published online: 31 July 2018
Elizabeth M. Cespedes Feliciano Egor Avrutin Bette J. Caan Adam Boroian Marina Mourtzakis
Screening for low muscularity in colorectal cancer patients: a valid, clinic-friendly approach that predicts mortality
Low skeletal muscle quantified using computed tomography (CT) scans is associated with morbidity and mortality among cancer patients. However, existing methods to assess skeletal muscle from CT are time-consuming, expensive, and require training. Clinic-friendly tools to screen for low skeletal muscle in cancer patients are urgently needed.
We included 807 scans from non-metastatic colorectal cancer patients. With the digital ruler available in most radiological software, we implemented an abbreviated method to assess skeletal muscle area at the third lumbar vertebra (L3), which consisted of assessing the height and width of the psoas and paraspinal muscles and computing their combined ‘linear area’ in centimetres squared (cm2). A subset of CT scans was assessed twice by two analysts to compute intra-rater and inter-rater reliability. We derived cut-points for ‘low’ linear area using optimal stratification and then calculated the sensitivity and specificity of these cut-points relative to standard methods (total L3 cross-sectional area assessed with Slice-O-Matic research software). We further evaluated the association of low linear area with death from any cause after colorectal cancer diagnosis in Cox proportional hazards models adjusting for demographics, smoking, body mass index category, and tumour characteristics.
The linear area was highly correlated with total cross-sectional area assessed using standard methods [r = 0.92; 95% confidence interval (CI): 0.91, 0.93] overall and within subgroups defined by age, sex, and body mass index group. Intra-rater and inter-rater reliability were equally high (both intra-class correlations = 0.98). Cut-points for low linear area were sensitive (0.75; 95% CI: 0.70, 0.80) and specific (0.77; 95% CI: 0.73, 0.80) for identifying low skeletal muscle relative to the standard of total L3 cross-sectional area. The hazard ratio and 95% CI for death associated with a low linear area were hazard ratio = 1.66; 95% CI: 1.22, 2.25.
Clinic-friendly methods that assess linear area from CT scans are an accurate screening tool to identify low skeletal muscle among non-metastatic colorectal cancer patients. These linear measures are associated with mortality after colorectal cancer, suggesting they could be clinically useful both to improve prognostication and to provide a practical screening tool to identify cancer patients who require nutrition or exercise intervention.
Cespedes Feliciano, E. M., Avrutin, E., Caan, B. J., Boroian, A., and Mourtzakis, M. (2018) Screening for low muscularity in colorectal cancer patients: a valid, clinic‐friendly approach that predicts mortality. Journal of Cachexia, Sarcopenia and Muscle, 9: 898–908. https://doi.org/10.1002/jcsm.12317.
Article first published online: 24 August 2018
Sophie A. Kurk, Petra H.M. Peeters, Bram Dorresteijn, Pim A. de Jong, Marion Jourdan, Hugo J. Kuijf, Cornelis J.A. Punt, Miriam Koopman, Anne M. May
Impact of different palliative systemic treatments on skeletal muscle mass in metastatic colorectal cancer patients
Observational studies suggest that loss of skeletal muscle mass (SMM) is associated with chemotherapy‐related toxicity, poor quality of life, and poor survival in metastatic colorectal cancer (mCRC) patients. Little is known about the evolution of SMM during palliative systemic therapy. We investigated changes in SMM during various consecutive palliative systemic treatment regimens using repeated abdominal computed tomography scans of mCRC patients who participated in the randomized phase 3 CAIRO3 study.
In the CAIRO3 study, mCRC patients with stable disease or better after 6 cycles of first‐line treatment with capecitabine + oxaliplatin + bevacizumab (CAPOX‐B) were randomized between maintenance treatment with capecitabine + bevacizumab (CAP‐B) or observation. Upon first disease progression, in both groups, CAPOX‐B or other treatment was reintroduced until the second disease progression, which was the primary study endpoint. We analysed 1355 computed tomography scans of 450 (81%) CAIRO3 patients (64 ± 9.0 years, CAP‐B n = 223; observation n = 227) for SMM at four time points (i.e. prior to the start of pre‐randomization initial treatment, at randomization, and at first and at second disease progression) using the Slice‐o‐matic software and single slice evaluation at the lumbar 3 level. By using accepted and widely used formulas, whole body SMM was calculated. A linear mixed effects model, adjusted for relevant confounders, was used to assess SMM changes for the total group and within and between study arms.
During 6 cycles of initial treatment with CAPOX‐B prior to randomization, SMM decreased significantly in all patients [CAP‐B arm: −0.53 kg (95% CI −1.12; −0.07) and observation arm: −0.85 kg (−1.45; −0.25)]. After randomization, SMM recovered during CAP‐B treatment by 1.32 kg (0.73; 1.90) and observation by 1.20 kg (0.63; 1.78) (median time from randomization to first disease progression 8.6 and 4.1 months for CAP‐B arm and observation arm, respectively). After first progression and during reintroduction treatment with CAPOX‐B or other treatment, SMM again decreased significantly and comparable in both arms, CAP‐B: −2.71 kg (−3.37; −2.03), and observation: −2.01 kg (−2.64; −1.41) (median time from first progression until second progression CAP‐B arm: 4.7 months and observation arm: 6.6 months).
This longitudinal study provides a unique insight in SMM changes in mCRC patients during palliative systemic treatment regimens, including observation. Our data show that muscle loss is reversible and may be influenced by the intensity of systemic regimens. Although studies have shown prognostic capacity for SMM, the effects of subsequent changes in SMM are unknown and may be clues for new future therapeutic interventions.
Kurk, S. A., Peeters, P. H. M., Dorresteijn, B., de Jong, P. A., Jourdan, M., Kuijf, H. J., Punt, C. J. A., Koopman, M., and May, A. M. (2018) Impact of different palliative systemic treatments on skeletal muscle mass in metastatic colorectal cancer patients. Journal of Cachexia, Sarcopenia and Muscle, 9: 909–919. https://doi.org/10.1002/jcsm.12337.
Article first published online: 16 September 2018
Ayse Zengin Landing M. Jarjou Ann Prentice Cyrus Cooper Peter R. Ebeling Kate A. Ward
The prevalence of sarcopenia and relationships between muscle and bone in ageing West-African Gambian men and women
The rapidly rising ageing population in low and middle-income countries (LMIC) will lead to a concurrent increase in musculoskeletal diseases. Sarcopenia is a disease caused by progressive loss of skeletal muscle mass and strength, leading to adverse outcomes including frailty, falls, fractures, and premature mortality. We investigated the prevalence of sarcopenia, assessed the suitability of current diagnostic guidelines and explored muscle–bone relationships in ageing men and women from rural Gambia.
A total of 249 women and 239 men aged 40–75+ years were recruited. Body composition was measured using dual energy X-ray absorptiometry. Comparisons of the Foundations for the National Institutes of Health (FNIH) and European Working Group On Sarcopenia (EWGSOP) definitions of sarcopenia to define prevalence and to identify poor physical capability were determined. Functional ability was assessed by jumping mechanography to calculate lower limb muscle force and power; grip strength was assessed by a hand dynamometer. Peripheral quantitative computed tomography was used to assess muscle–bone relationships.
The prevalence of sarcopenia in Gambian men and women significantly varied depending on the definition used; in men 20% and 19% and in women 45% and 10% for FNIH and EWGSOP, respectively. The FNIH appendicular lean mass cut-off had greatest sensitivity and specificity in identifying low functional ability in Gambian adults. Muscle force was positively associated with measures of tibial bone size, strength, and mineral content.
The variation in the prevalence of sarcopenia depends on the definition used and highlights the importance of measuring functional capability across ethnic populations.
Zengin, A., Jarjou, L. M., Prentice, A., Cooper, C., Ebeling, P. R., and Ward, K. A. (2018) The prevalence of sarcopenia and relationships between muscle and bone in ageing West‐African Gambian men and women. Journal of Cachexia, Sarcopenia and Muscle, 9: 920–928. https://doi.org/10.1002/jcsm.12341.
Article first published online: 10 July 2018
Marine Gueugneau, Donatienne d'Hose, Caroline Barbé, Marie de Barsy, Pascale Lause, Dominique Maiter, Laure B. Bindels, Nathalie M. Delzenne, Laurent Schaeffer, Yann-Gaël Gangloff, Christophe Chambon, Cécile Coudy-Gandilhon, Daniel Béchet, Jean-Paul Thissen
Increased Serpina3n release into circulation during glucocorticoid-mediated muscle atrophy
Glucocorticoids (GC) play a major role in muscle atrophy. As skeletal muscle is a secretory organ, characterization of the muscle secretome elicited by muscle atrophy should allow to better understand the cellular mechanisms and to identify circulating biomarkers of this condition. Our project aimed to identify the changes in the muscle secretome associated with GC-induced muscle atrophy and susceptible to translate into circulation.
We have identified the GC-induced changes in the secretome of C2C12 muscle cells by proteomic analysis, and then, we have determined how these changes translate into the circulation of mice or human subjects exposed to high concentrations of GC.
This approach led us to identify Serpina3n as one of the most markedly secreted protein in response to GC. Our original in vitro results were confirmed in vivo by an increased expression of Serpina3n in skeletal muscle (3.9-fold; P < 0.01) and in the serum (two-fold; P < 0.01) of mice treated with GC. We also observed increased levels of the human orthologue Serpina3 in the serum of Cushing's syndrome patients compared with healthy controls matched for age and sex (n = 9/group, 2.5-fold; P < 0.01). An increase of Serpina3n was also demonstrated in muscle atrophy models mediated by GC such as cancer cachexia (four-fold; P < 0.01), sepsis (12.5-fold; P < 0.001), or diabetes (two-fold; P < 0.01). In contrast, levels of Serpina3n both in skeletal muscle and in the circulation were reduced in several models of muscle hypertrophy induced by myostatin inhibition (P < 0.01). Furthermore, a cluster of data suggests that the regulation of muscle Serpina3n involves mTOR, an essential determinant of the muscle cell size.
Taken together, these data suggest that Serpina3n may represent a circulating biomarker of muscle atrophy associated to GC and, broadly, a reflection of dynamic changes in muscle mass.
Gueugneau, M., d'Hose, D., Barbé, C., de Barsy, M., Lause, P., Maiter, D., Bindels, L. B., Delzenne, N. M., Schaeffer, L., Gangloff, Y.‐G., Chambon, C., Coudy‐Gandilhon, C., Béchet, D., and Thissen, J.‐P. (2018) Increased Serpina3n release into circulation during glucocorticoid‐mediated muscle atrophy. Journal of Cachexia, Sarcopenia and Muscle, 9: 929–946. https://doi.org/10.1002/jcsm.12315.
Article first published online: 05 July 2018
Robbert van der Pijl, Joshua Strom, Stefan Conijn, Johan Lindqvist, Siegfried Labeit, Henk Granzier, Coen Ottenheijm
Titin-based mechanosensing modulates muscle hypertrophy
Titin is an elastic sarcomeric filament that has been proposed to play a key role in mechanosensing and trophicity of muscle. However, evidence for this proposal is scarce due to the lack of appropriate experimental models to directly test the role of titin in mechanosensing.
We used unilateral diaphragm denervation (UDD) in mice, an in vivo model in which the denervated hemidiaphragm is passively stretched by the contralateral, innervated hemidiaphragm and hypertrophy rapidly occurs.
In wildtype mice, the denervated hemidiaphragm mass increased 48 ± 3% after 6 days of UDD, due to the addition of both sarcomeres in series and in parallel. To test whether titin stiffness modulates the hypertrophy response, RBM20?RRM and Ttn?IAjxn mouse models were used, with decreased and increased titin stiffness, respectively. RBM20?RRM mice (reduced stiffness) showed a 20 ± 6% attenuated hypertrophy response, whereas the Ttn?IAjxn mice (increased stiffness) showed an 18 ± 8% exaggerated response after UDD. Thus, muscle hypertrophy scales with titin stiffness. Protein expression analysis revealed that titin-binding proteins implicated previously in muscle trophicity were induced during UDD, MARP1 & 2, FHL1, and MuRF1.
Titin functions as a mechanosensor that regulates muscle trophicity.
van der Pijl, R., Strom, J., Conijn, S., Lindqvist, J., Labeit, S., Granzier, H., and Ottenheijm, C. (2018) Titin‐based mechanosensing modulates muscle hypertrophy. Journal of Cachexia, Sarcopenia and Muscle, 9: 947–961. https://doi.org/10.1002/jcsm.12319.
Article first published online: 24 July 2018
Lijing Sun, Meijun Si, Xinyan Liu, Jong Min Choi, Yanlin Wang, Sandhya S. Thomas, Hui Peng, Zhaoyong Hu
Long-noncoding RNA Atrolnc-1 promotes muscle wasting in mice with chronic kidney disease
Chronic kidney disease (CKD) is commonly associated with cachexia, a condition that causes skeletal muscle wasting and an unfavourable prognosis. Although mechanisms leading to cachexia have been intensively studied, the advance of biological knowledges and technologies encourages us to make progress in understanding the pathogenesis of this disorder. Long noncoding RNAs (lncRNAs) are defined as >200 nucleotides RNAs but lack the protein-coding potential. LncRNAs are involved in the pathogenesis of many diseases, but whether they functionally involve in muscle protein loss has not been investigated.
We performed lncRNA array and identified an lncRNA, which we named Atrolnc-1, remarkably elevated in atrophying muscles from mice with cachexia. We examined how overexpression or knockdown of Atrolnc-1 could influence muscle protein synthesis and degradation. We also examined whether inhibition of Atrolnc-1 ameliorates muscle wasting in mice with CKD.
We documented that Atrolnc-1 expression is continuously increased in muscles of mice with fasting (5.4 fold), cancer (2.0 fold), or CKD (5.1 fold). We found that depressed insulin signalling stimulates the transcription factor C/EBP-a binding to the promoter of Atrolnc-1 and promotes the expression of Atrolnc-1. In cultured C2C12 myotubes, overexpression of Atrolnc-1 increases protein degradation (0.45±0.03 vs. 0.64±0.02, *p<0.05); Atrolnc-1 knockdown significantly reduces the rate of protein degradation stimulated by serum depletion (0.61±0.03 vs. 0.47±0.02, *p<0.05). Using mass spectrometry and a lncRNA pull-down assay, we identified that Atrolnc-1 interacts with A20 binding inhibitor of NF-?B-1 (ABIN-1). The interaction impairs function, resulting in enhanced NF-?B activity plus MuRF-1 transcription. This response is counteracted by CRISPR/dCas9 mediated overexpression. In muscles from normal mice, overexpression of Atrolnc-1 stimulates a 2.7-fold increase in MuRF-1 expression leading to myofibers atrophy. In contrast, Atrolnc-1 knockdown attenuates muscle wasting by 42% in mice with CKD via suppression of NF-?B activity and MuRF-1 expression.
Our findings provide evidence that lncRNAs initiates the pathophysiological process of muscle wasting. The interaction between Atrolnc-1 and NF-?B signalling modulates muscle mass and proteolysis in CKD and perhaps other catabolic conditions.
Sun, L., Si, M., Liu, X., Choi, J. M., Wang, Y., Thomas, S. S., Peng, H., and Hu, Z. (2018) Long‐noncoding RNA Atrolnc‐1 promotes muscle wasting in mice with chronic kidney disease. Journal of Cachexia, Sarcopenia and Muscle, 9: 962–974. https://doi.org/10.1002/jcsm.12321.
Article first published online: 11 September 2018
Hikari Takeshita, Koichi Yamamoto, Satoko Nozato, Masao Takeda, So-ichiro Fukada, Tadakatsu Inagaki, Hirotsugu Tsuchimochi, Mikiyasu Shirai, Yoichi Nozato, Taku Fujimoto, Yuki Imaizumi, Serina Yokoyama, Motonori Nagasawa, Go Hamano, Kazuhiro Hongyo, Tatsuo Kawai, Hiroko Hanasaki-Yamamoto, Shuko Takeda, Toshimasa Takahashi, Hiroshi Akasaka, Norihisa Itoh, Yoichi Takami, Yasushi Takeya, Ken Sugimoto, Hironori Nakagami, Hiromi Rakugi
Angiotensin-converting enzyme 2 deficiency accelerates and angiotensin 1-7 restores age-related muscle weakness in mice
A pharmacologic strategy for age-related muscle weakness is desired to improve mortality and disability in the elderly. Angiotensin-converting enzyme 2 (ACE2) cleaves angiotensin II into angiotensin 1-7, a peptide known to protect against acute and chronic skeletal muscle injury in rodents. Since physiological aging induces muscle weakness via mechanisms distinct from other muscle disorders, the role of ACE2-angiotensin 1-7 in age-related muscle weakness remains undetermined. Here, we investigated whether deletion of ACE2 alters the development of muscle weakness by aging and whether angiotensin 1-7 reverses muscle weakness in older mice.
After periodic measurement of grip strength and running distance in male ACE2KO and wild-type mice until 24?months of age, we infused angiotensin 1-7 or vehicle for 4?weeks, and measured grip strength, and excised tissues. Tissues were also excised from younger (3-month-old) and middle-aged (15-month-old) mice. Microarray analysis of RNA was performed using tibialis anterior (TA) muscles from middle-aged mice, and some genes were further tested using RT-PCR.
Grip strength of ACE2KO mice was reduced at 6?months and was persistently lower than that of wild-type mice (p?Conclusions
Deletion of ACE2 induced the early manifestation of muscle weakness with signatures of muscle senescence. Angiotensin 1-7 improved muscle function in older mice, supporting future application of the peptide or its analogues in the treatment of muscle weakness in the elderly population.
Takeshita, H., Yamamoto, K., Nozato, S., Takeda, M., Fukada, S., Inagaki, T., Tsuchimochi, H., Shirai, M., Nozato, Y., Fujimoto, T., Imaizumi, Y., Yokoyama, S., Nagasawa, M., Hamano, G., Hongyo, K., Kawai, T., Hanasaki‐Yamamoto, H., Takeda, S., Takahashi, T., Akasaka, H., Itoh, N., Takami, Y., Takeya, Y., Sugimoto, K., Nakagami, H., and Rakugi, H. (2018) Angiotensin‐converting enzyme 2 deficiency accelerates and angiotensin 1‐7 restores age‐related muscle weakness in mice. Journal of Cachexia, Sarcopenia and Muscle, 9: 975–986. https://doi.org/10.1002/jcsm.12334.
Article first published online: 16 October 2018
Jacob L. Brown, David E. Lee, Megan E. Rosa‐Caldwell, Lemuel A. Brown, Richard A. Perry, Wesley S. Haynie, Kendra Huseman, Kavithalakshmi Sataranatarajan, Holly Van Remmen, Tyrone A. Washington, Michael P. Wiggs, Nicholas P. Greene
Protein imbalance in the development of skeletal muscle wasting in tumour‐bearing mice
Cancer cachexia occurs in approximately 80% of cancer patients and is a key contributor to cancer‐related death. The mechanisms controlling development of tumour‐induced muscle wasting are not fully elucidated. Specifically, the progression and development of cancer cachexia are underexplored. Therefore, we examined skeletal muscle protein turnover throughout the development of cancer cachexia in tumour‐bearing mice.
Lewis lung carcinoma (LLC) was injected into the hind flank of C57BL6/J mice at 8 weeks age with tumour allowed to develop for 1, 2, 3, or 4 weeks and compared with PBS injected control. Muscle size was measured by cross‐sectional area analysis of haematoxylin and eosin stained tibialis anterior muscle. 2H2O was used to assess protein synthesis throughout the development of cancer cachexia. Immunoblot and RT‐qPCR were used to measure regulators of protein turnover. TUNEL staining was utilized to measure apoptotic nuclei. LLC conditioned media (LCM) treatment of C2C12 myotubes was used to analyse cancer cachexia in vitro.
Muscle cross‐sectional area decreased ~40% 4 weeks following tumour implantation. Myogenic signalling was suppressed in tumour‐bearing mice as soon as 1 week following tumour implantation, including lower mRNA contents of Pax7, MyoD, CyclinD1, and Myogenin, when compared with control animals. AchRδ and AchRε mRNA contents were down‐regulated by ~50% 3 weeks following tumour implantation. Mixed fractional synthesis rate protein synthesis was ~40% lower in 4 week tumour‐bearing mice when compared with PBS controls. Protein ubiquitination was elevated by ~50% 4 weeks after tumour implantation. Moreover, there was an increase in autophagy machinery after 4 weeks of tumour growth. Finally, ERK and p38 MAPK phosphorylations were fourfold and threefold greater than control muscle 4 weeks following tumour implantation, respectively. Inhibition of p38 MAPK, but not ERK MAPK, in vitro partially rescued LCM‐induced loss of myotube diameter.
Our findings work towards understanding the pathophysiological signalling in skeletal muscle in the initial development of cancer cachexia. Shortly following the onset of the tumour‐bearing state alterations in myogenic regulatory factors are apparent, suggesting early onset alterations in the capacity for myogenic induction. Cancer cachexia presents with a combination of a loss of protein synthesis and increased markers of protein breakdown, specifically in the ubiquitin‐proteasome system. Also, p38 MAPK may be a potential therapeutic target to combat cancer cachexia via a p38‐FOX01‐atrogene‐ubiquitin‐proteasome mechanism.
Brown, J. L., Lee, D. E., Rosa‐Caldwell, M. E., Brown, L. A., Perry, R. A., Haynie, W. S., Huseman, K., Sataranatarajan, K., Van Remmen, H., Washington, T. A., Wiggs, M. P., and Greene, N. P. (2018) Protein imbalance in the development of skeletal muscle wasting in tumour‐bearing mice. Journal of Cachexia, Sarcopenia and Muscle, 9: 987–1002. https://doi.org/10.1002/jcsm.12354.
Article first published online: 2 August 2018
Rizwan Qaisar, Shylesh Bhaskaran, Pavithra Premkumar, Rojina Ranjit, Kavithalakshmi Satara Natarajan, Bumsoo Ahn, Kaitlyn Riddle, Dennis R. Claflin, Arlan Richardson Susan V. Brooks, Holly Van Remme
Oxidative stress-induced dysregulation of excitation–contraction coupling contributes to muscle weakness
We have previously shown that the deletion of the superoxide scavenger, CuZn superoxide dismutase, in mice (Sod1-/- mice) results in increased oxidative stress and an accelerated loss of skeletal muscle mass and force that mirror the changes seen in old control mice. The goal of this study is to define the effect of oxidative stress and ageing on muscle weakness and the Excitation Contraction (EC) coupling machinery in age-matched adult (8–10 months) wild-type (WT) and Sod1-/- mice in comparison with old (25–28 months) WT mice.
In vitro contractile assays were used to measure muscle contractile parameters. The activity of the sarcoplasmic reticulum Ca2+ ATPase (SERCA) pump was measured using an NADH-linked enzyme assay. Immunoblotting and immunofluorescence techniques were used to measure protein expression, and real-time reverse transcription PCR was used to measure gene expression.
The specific force generated by the extensor digitorum longus muscle was reduced in the Sod1-/- and old WT mice compared with young WT mice along with significant prolongation of time to peak force, increased half relaxation time, and disruption of intracellular calcium handling. The maximal activity of the SERCA calcium uptake pump was significantly reduced in gastrocnemius muscle from both old WT (˜14%) and adult Sod1-/- (˜33%) mice compared with young WT mice along with increased expression of sarcolipin, a known inhibitor of SERCA activity. Protein levels of the voltage sensor and calcium uptake channel proteins dihydropyridine receptor a1 and SERCA2 were significantly elevated (˜45% and ˜57%, respectively), while the ratio of calstabin, a channel stabilizing protein, to ryanodine receptor was significantly reduced (˜21%) in Sod1-/- mice compared with young WT mice. The changes in calcium handling were accompanied by substantially elevated levels of global protein carbonylation and lipid peroxidation.
Our data suggest that the muscle weakness in Sod1-/- and old WT mice is in part driven by reactive oxygen species-mediated EC uncoupling and supports a role for reduced SERCA pump activity in compromised muscle function. The novel quantitative mechanistic data provided here can lead to potential therapeutic interventions of SERCA dysfunction for sarcopenia and muscle diseases.
Qaisar, R., Bhaskaran, S., Premkumar, P., Ranjit, R., Natarajan, K. S., Ahn, B., Riddle, K., Claflin, D. R., Richardson, A., Brooks, S. V., and Van Remmen, H. (2018) Oxidative stress‐induced dysregulation of excitation–contraction coupling contributes to muscle weakness. Journal of Cachexia, Sarcopenia and Muscle, 9: 1003–1017. https://doi.org/10.1002/jcsm.12339.