bims-aucach Biomed News
on Autophagy and cachexia
Issue of 2022–02–27
seventeen papers selected by
Kleiton Silva, Rowan University
  1. Iron supplementation is sufficient to rescue skeletal muscle mass and function in cancer cachexia.
  2. Metabolomics and its Applications in Cancer Cachexia.
  3. Addressing unmet needs for people with cancer cachexia: recommendations from a multistakeholder workshop.
  4. Autophagy and cancer treatment: four functional forms of autophagy and their therapeutic applications.
  5. Interleukin-6 potentiates endurance training adaptation and improves functional capacity in old mice.
  6. Extracellular Vesicles in Redox Signaling and Metabolic Regulation in Chronic Kidney Disease.
  7. Effect of exercise on pancreatic cancer patients during treatment: a scoping review of the literature.
  8. Interleukin 6 as an energy allocator in muscle tissue.
  9. Possible Benefits of a Low Protein Diet in Older Patients With CKD at Risk of Malnutrition: A Pilot Randomized Controlled Trial.
  10. Effect of an aerobic and strength exercise combined program on oxidative stress and inflammatory biomarkers in patients undergoing hemodialysis: a single blind randomized controlled trial.
  11. Enhanced Autophagic Flux, Suppressed Apoptosis and Reduced Macrophage Infiltration by Dasatinib in Kidneys of Obese Mice.
  12. Serum irisin level is independent of sarcopenia and related muscle parameters in older adults.
  13. Clinical practice guideline exercise and lifestyle in chronic kidney disease.
  14. Gait disorders in CKD patients: muscle wasting or cognitive impairment? A cross-sectional pilot study to investigate gait signatures in Stage 1-5 CKD patients.
  15. The Panax ginseng Berry Extract and Soluble Whey Protein Hydrolysate Mixture Ameliorates Sarcopenia-Related Muscular Deterioration in Aged Mice.
  16. Application of the Clinical Frailty Score and body composition and upper arm strength in haemodialysis patients.
  17. Autophagy-related prognostic signature for survival prediction of triple negative breast cancer.
  1. EMBO Rep. 2022 Feb 24. e53746
    Iron supplementation is sufficient to rescue skeletal muscle mass and function in cancer cachexia.
    Elisabeth Wyart, Myriam Y Hsu, Roberta Sartori, Erica Mina, Valentina Rausch, Elisa S Pierobon, Mariarosa Mezzanotte, Camilla Pezzini, Laure B Bindels, Andrea Lauria, Fabio Penna, Emilio Hirsch, Miriam Martini, Massimiliano Mazzone, Antonella Roetto, Simonetta Geninatti Crich, Hans Prenen, Marco Sandri, Alessio Menga, Paolo E Porporato.
      Cachexia is a wasting syndrome characterized by devastating skeletal muscle atrophy that dramatically increases mortality in various diseases, most notably in cancer patients with a penetrance of up to 80%. Knowledge regarding the mechanism of cancer-induced cachexia remains very scarce, making cachexia an unmet medical need. In this study, we discovered strong alterations of iron metabolism in the skeletal muscle of both cancer patients and tumor-bearing mice, characterized by decreased iron availability in mitochondria. We found that modulation of iron levels directly influences myotube size in vitro and muscle mass in otherwise healthy mice. Furthermore, iron supplementation was sufficient to preserve both muscle function and mass, prolong survival in tumor-bearing mice, and even rescues strength in human subjects within an unexpectedly short time frame. Importantly, iron supplementation refuels mitochondrial oxidative metabolism and energy production. Overall, our findings provide new mechanistic insights in cancer-induced skeletal muscle wasting, and support targeting iron metabolism as a potential therapeutic option for muscle wasting diseases.
    Keywords:  cachexia; iron; metabolism; mitochondria; muscle
    DOI:  https://doi.org/10.15252/embr.202153746
  2. Front Mol Biosci. 2022 ;9 789889
    Metabolomics and its Applications in Cancer Cachexia.
    Pengfei Cui, Xiaoyi Li, Caihua Huang, Qinxi Li, Donghai Lin.
      Cancer cachexia (CC) is a complicated metabolic derangement and muscle wasting syndrome, affecting 50-80% cancer patients. So far, molecular mechanisms underlying CC remain elusive. Metabolomics techniques have been used to study metabolic shifts including changes of metabolite concentrations and disturbed metabolic pathways in the progression of CC, and expand further fundamental understanding of muscle loss. In this article, we aim to review the research progress and applications of metabolomics on CC in the past decade, and provide a theoretical basis for the study of prediction, early diagnosis, and therapy of CC.
    Keywords:  biomarker; cancer cachexia; metabolic alterations; metabolomics; progress
    DOI:  https://doi.org/10.3389/fmolb.2022.789889
  3. J Cachexia Sarcopenia Muscle. 2022 Feb 26.
    Addressing unmet needs for people with cancer cachexia: recommendations from a multistakeholder workshop.
    Jose M Garcia, Richard F Dunne, Kristen Santiago, Lisa Martin, Morris J Birnbaum, Jeffrey Crawford, Andrew E Hendifar, Martin Kochanczyk, Cassadie Moravek, Doris Piccinin, Vincent Picozzi, Eric J Roeland, Wendy K D Selig, Teresa A Zimmers.
      
    Keywords:  Cachexia; Cancer; Cholangiocarcinoma; Colorectal cancer; Congress; Lung cancer; Nutrition; Pancreatic cancer; Supportive care
    DOI:  https://doi.org/10.1002/jcsm.12910
  4. J Zhejiang Univ Sci B. 2022 Feb 15. pii: 1673-1581(2022)02-0089-13. [Epub ahead of print]23(2): 89-101
    Autophagy and cancer treatment: four functional forms of autophagy and their therapeutic applications.
    Zhaoshi Bai, Yaling Peng, Xinyue Ye, Zhixian Liu, Yupeng Li, Lingman Ma.
      Cancer is the leading cause of death worldwide. Drugs play a pivotal role in cancer treatment, but the complex biological processes of cancer cells seriously limit the efficacy of various anticancer drugs. Autophagy, a self-degradative system that maintains cellular homeostasis, universally operates under normal and stress conditions in cancer cells. The roles of autophagy in cancer treatment are still controversial because both stimulation and inhibition of autophagy have been reported to enhance the effects of anticancer drugs. Thus, the important question arises as to whether we should try to strengthen or suppress autophagy during cancer therapy. Currently, autophagy can be divided into four main forms according to its different functions during cancer treatment: cytoprotective (cell survival), cytotoxic (cell death), cytostatic (growth arrest), and nonprotective (no contribution to cell death or survival). In addition, various cell death modes, such as apoptosis, necrosis, ferroptosis, senescence, and mitotic catastrophe, all contribute to the anticancer effects of drugs. The interaction between autophagy and these cell death modes is complex and can lead to anticancer drugs having different or even completely opposite effects on treatment. Therefore, it is important to understand the underlying contexts in which autophagy inhibition or activation will be beneficial or detrimental. That is, appropriate therapeutic strategies should be adopted in light of the different functions of autophagy. This review provides an overview of recent insights into the evolving relationship between autophagy and cancer treatment.
    Keywords:  Autophagy; Cancer treatment; Cell death mode; Precision treatment
    DOI:  https://doi.org/10.1631/jzus.B2100804
  5. J Cachexia Sarcopenia Muscle. 2022 Feb 22.
    Interleukin-6 potentiates endurance training adaptation and improves functional capacity in old mice.
    Aurel B Leuchtmann, Regula Furrer, Stefan A Steurer, Konstantin Schneider-Heieck, Bettina Karrer-Cardel, Yves Sagot, Christoph Handschin.
       BACKGROUND: Interventions to preserve functional capacities at advanced age are becoming increasingly important. So far, exercise provides the only means to counteract age-related decrements in physical performance and muscle function. Unfortunately, the effectiveness of exercise interventions in elderly populations is hampered by reduced acceptance and compliance as well as disuse complications. We therefore studied whether application of interleukin-6 (IL-6), a pleiotropic myokine that is induced by skeletal muscle activity and exerts broad systemic effects in response to exercise, affects physical performance and muscle function alone or in combination with training in aged mice.
    METHODS: Sedentary old male mice (Sed+Saline, n = 15) were compared with animals that received recombinant IL-6 (rIL-6) in an exercise-mimicking pulsatile manner (Sed+IL-6, n = 16), were trained with a moderate-intensity, low-volume endurance exercise regimen (Ex+Saline, n = 13), or were exposed to a combination of these two interventions (Ex+IL-6, n = 16) for 12 weeks. Before and at the end of the intervention, mice underwent a battery of tests to quantify endurance performance, muscle contractility in situ, motor coordination, and gait and metabolic parameters.
    RESULTS: Mice exposed to enhanced levels of IL-6 during endurance exercise bouts showed superior improvements in endurance performance (33% more work and 12% greater peak power compared with baseline), fatigue resistance in situ (P = 0.0014 vs. Sed+Saline; P = 0.0199 vs. Sed+IL-6; and P = 0.0342 vs. Ex+Saline), motor coordination (rotarod performance, P = 0.0428), and gait (gait speed, P = 0.0053) following training. Pulsatile rIL-6 treatment in sedentary mice had only marginal effects on glucose tolerance and some gait parameters. No increase in adverse events or mortality related to rIL-6 treatment was observed.
    CONCLUSIONS: Administration of rIL-6 paired with treadmill running bouts potentiates the adaptive response to a moderate-intensity low-volume endurance exercise regimen in old mice, while being safe and well tolerated.
    Keywords:  Ageing; Exercise; Fatigue; Frailty; Interleukin-6; Muscle; Myokine
    DOI:  https://doi.org/10.1002/jcsm.12949
  6. Antioxidants (Basel). 2022 Feb 11. pii: 356. [Epub ahead of print]11(2):
    Extracellular Vesicles in Redox Signaling and Metabolic Regulation in Chronic Kidney Disease.
    Omar Emiliano Aparicio-Trejo, Ana Karina Aranda-Rivera, Horacio Osorio-Alonso, Elena Martínez-Klimova, Laura Gabriela Sánchez-Lozada, José Pedraza-Chaverri, Edilia Tapia.
      Chronic kidney disease (CKD) is a world health problem increasing dramatically. The onset of CKD is driven by several mechanisms; among them, metabolic reprogramming and changes in redox signaling play critical roles in the advancement of inflammation and the subsequent fibrosis, common pathologies observed in all forms of CKD. Extracellular vesicles (EVs) are cell-derived membrane packages strongly associated with cell-cell communication since they transfer several biomolecules that serve as mediators in redox signaling and metabolic reprogramming in the recipient cells. Recent studies suggest that EVs, especially exosomes, the smallest subtype of EVs, play a fundamental role in spreading renal injury in CKD. Therefore, this review summarizes the current information about EVs and their cargos' participation in metabolic reprogramming and mitochondrial impairment in CKD and their role in redox signaling changes. Finally, we analyze the effects of these EV-induced changes in the amplification of inflammatory and fibrotic processes in the progression of CKD. Furthermore, the data suggest that the identification of the signaling pathways involved in the release of EVs and their cargo under pathological renal conditions can allow the identification of new possible targets of injury spread, with the goal of preventing CKD progression.
    Keywords:  chronic kidney disease; exosomes; extracellular vesicles; fibrosis; inflammation; lipotoxicity; metabolic reprogramming; microvesicles; mitochondrial impairment; oxidative stress; redox signaling
    DOI:  https://doi.org/10.3390/antiox11020356
  7. Support Care Cancer. 2022 Feb 21.
    Effect of exercise on pancreatic cancer patients during treatment: a scoping review of the literature.
    Priti Gupta, Charles F Hodgman, Keri L Schadler, Emily C LaVoy.
       INTRODUCTION: Exercise can lower the risk of developing pancreatic cancer and has the potential to improve physical fitness and quality of life in patients with the disease. Yet, the effects of exercise training during pancreatic cancer treatment remain poorly characterized. This hampers the development of evidence-based disease-specific exercise recommendations.
    PURPOSE: The purpose of this review was to describe and interpret the effect of exercise on physiological, QoL, and cancer-specific outcomes reported in clinical trials among pancreatic cancer patients during treatment.
    METHODS: We conducted a scoping review of the literature according to the framework proposed by Arksey and O'Malley. Articles published prior to December 2021 were retrieved from PubMed, EMBASE, and Scopus. We only included studies that prescribed structured cardiorespiratory and/or resistance exercise in pancreatic cancer patients undergoing treatment.
    RESULTS: A total of 662 references were retrieved, of which 24 are included in the review. Twelve articles were randomized controlled trials and 12 were single-arm trials. Overlap in the trials from which data were reported occurred in 16 articles. Moderate intensity exercise was most commonly prescribed, reported feasible for most patients, with potential to enhance physical fitness and QoL. However, exercise adherence and beneficial effects may diminish with disease progression. Limited evidence suggests exercise may benefit cancer-specific outcomes.
    CONCLUSION: The results of this review indicate that exercise is feasible during pancreatic cancer treatment. Exercise can also improve physical fitness and QoL. However, its beneficial effects may fall with advanced disease and more rigorous research is needed to develop precise exercise protocols for this population.
    Keywords:  Chemoradiation; Chemotherapy; Pancreatic Neoplasms; Physical activity; Prehabilitation
    DOI:  https://doi.org/10.1007/s00520-022-06925-7
  8. Nat Metab. 2022 Feb 24.
    Interleukin 6 as an energy allocator in muscle tissue.
    Timothy M Kistner, Bente K Pedersen, Daniel E Lieberman.
      Extensive research has shown that interleukin 6 (IL-6) is a multifunctional molecule that is both proinflammatory and anti-inflammatory, depending on the context. Here, we combine an evolutionary perspective with physiological data to propose that IL-6's context-dependent effects on metabolism reflect its adaptive role for short-term energy allocation. This energy-allocation role is especially salient during physical activity, when skeletal muscle releases large amounts of IL-6. We predict that during bouts of physical activity, myokine IL-6 fulfills the three main characteristics of a short-term energy allocator: it is secreted from muscle in response to an energy deficit, it liberates somatic energy through lipolysis and it enhances muscular energy uptake and transiently downregulates immune function. We then extend this model of energy allocation beyond myokine IL-6 to reinterpret the roles that IL-6 plays in chronic inflammation, as well as during COVID-19-associated hyperinflammation and multiorgan failure.
    DOI:  https://doi.org/10.1038/s42255-022-00538-4
  9. Front Nutr. 2021 ;8 782499
    Possible Benefits of a Low Protein Diet in Older Patients With CKD at Risk of Malnutrition: A Pilot Randomized Controlled Trial.
    Lara Caldiroli, Simone Vettoretti, Silvia Armelloni, Deborah Mattinzoli, Masami Ikehata, Paolo Molinari, Carlo Alfieri, Piergiorgio Messa, Giuseppe Castellano.
       Background: Current guidelines do not clarify whether older patients with advanced chronic kidney disease (CKD) may benefit of low protein (LP) diet if they are at risk of malnutrition. We compared the effects of normocalorie/normoprotein (NP) and normocalorie/LP diet on nutritional status and metabolic complications related to the progression of kidney damage in these patients.
    Methods: This pilot study had an open-label randomized-controlled design (ClinicalTrials.gov Id: NCT05015647). Thirty-five patients were treated for 6 months with two different diets (LP = 17) and (NP = 18). Malnutrition was assessed by the Malnutrition Inflammation Score and International Society of Renal Nutrition and Metabolism criteria. Renal function was assessed by creatinine and cystatin-C-based estimated glomerular filtration rate (eGFR).
    Results: At the end of the study, Malnutrition Inflammation Score was improved in both LP and NP groups (respectively: 3 ± 3 vs. 6 ± 1.5, p = 0.020 and 3 ± 2.5 vs. 6 ± 2, p = 0.012), prevalence of protein energy wasting syndrome decreased only in LP. LP group had higher eGFRcys-C (17 ± 6 vs. 12 ± 4 ml/min/1.73 m2; p < 0.05), lower serum urea (105 ± 65 vs. 138 ± 30 mg/dl; p < 0.05) and lower parathormone (68 ± 10 vs. 99 ± 61 ng/L; p < 0.05) than NP. Serum and urinary phosphorous did not change while fibroblast growth factor 23 (FGF23)-intact and FGF23 c-terminal increased in both groups [FGF23-intact in LP: 70 (48; 98) vs. 126 (90; 410) pg/ml, p < 0.01 and in NP: 86 (57; 194) vs. 143 (119; 186) pg/ml, p < 0.01; FGF23 c-terminal in LP: 77 (30.3; 112) vs. 111 (63; 384) RU/ml, p < 0.01 and in NP: 142 (56.6; 175) vs. 157 (76.7; 281) RU/ml, p < 0.01].
    Conclusions: LP diet has a favorable impact on nutritional status as much as NP diet with possible greater benefits on the progression of kidney disease and some of its metabolic complications.
    Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT05015647, identifier: NCT05015647.
    Keywords:  FGF23; chronic kidney disease; inflammation; low protein diet; malnutrition
    DOI:  https://doi.org/10.3389/fnut.2021.782499
  10. Int Urol Nephrol. 2022 Feb 23.
    Effect of an aerobic and strength exercise combined program on oxidative stress and inflammatory biomarkers in patients undergoing hemodialysis: a single blind randomized controlled trial.
    Erika Meléndez-Oliva, Isabel Sánchez-Vera Gómez-Trelles, Eva Segura-Orti, Borja Pérez-Domínguez, Rafael García-Maset, Alicia García-Testal, Jose Luis Lavandera-Díaz.
       BACKGROUND: Chronic kidney disease patients on hemodialysis treatment are characterized by increased levels of inflammatory markers and oxidative stress, in addition to a significant deterioration in physical function. The benefits of physical exercise on the functional capacity of this patients are well known; however, it can also improve the endogenous antioxidant defense system and the inflammatory state, but still very few studies have been carried out. This is the first study to analyze the effect of a 4-month exercise program with combined aerobic and strength training in patients undergoing hemodialysis, under two modalities.
    METHODS: Seventy-one patients undergoing hemodialysis were enrolled and randomized in two groups, one of them performing an intra-dialysis exercise program (n = 36), and the other carrying out a home-based exercise program (n = 35). Serum levels of oxidative stress and inflammation biomarkers were determined before and after the intervention.
    RESULTS: IL-6 plasma levels showed a significant decrease in the intra-dialysis group after exercise (42.61 ± 9.21 to 26.40 ± 7.84, p = 0.03), while CRP levels decreased significantly in the home-based group (16.12 ± 24.18 to 8.50 ± 11.28, p = 0.03). MCP-1, TNF-α, ICAM-1 and the oxidative stress markers MDA, GSH and GSSG, did not undergo significant changes after the intervention.
    CONCLUSION: Four months of combined strength and aerobic endurance exercise improve the inflammatory status of hemodialysis patients by significantly reducing IL-6 levels in those subjects who perform intra-dialysis exercise and CRP levels in those who do it at home.
    Keywords:  Chronic renal disease; Exercise; Hemodialysis; Inflammation; Oxidative stress
    DOI:  https://doi.org/10.1007/s11255-022-03146-z
  11. Cells. 2022 Feb 21. pii: 746. [Epub ahead of print]11(4):
    Enhanced Autophagic Flux, Suppressed Apoptosis and Reduced Macrophage Infiltration by Dasatinib in Kidneys of Obese Mice.
    Hassan Reda Hassan Elsayed, Randa El-Gamal, Mohammed R Rabei, Mona G Elhadidy, Shereen Hamed, Basma H Othman, Mohamed Mahmoud Abdelraheem Elshaer, Mostafa Khaled Sedky, Ahmed Tarek Abd Elbaset Hassan, Mohammad El-Nablaway.
      Obesity causes renal changes (ORC), characterized by defective renal autophagy, lipogenesis, enhanced macrophage infiltration and apoptosis. We hypothesize that Dasatinib, a tyrosine kinase inhibitor, may ameliorate changes associated with obesity. We the mice with either Obesogenic diet (OD) or a standard basal diet. After 12 weeks, the mice received either vehicle or Dasatinib 4 mg/kg/d for an additional four weeks. We examined serum creatinine, urea, lipid profile and renal cortical mRNA expression for lipogenesis marker SREBP1, inflammatory macrophage marker iNOS and fibrosis markers; TGFβ and PDGFA genes; immunohistochemical (IHC) staining for CD68; inflammatory macrophage marker and ASMA; fibrosis marker, LC3 and SQSTM1/P62; autophagy markers and western blotting (WB) for caspase-3; and, as an apoptosis marker, LC3II/I and SQSTM1/P62 in addition to staining for H&E, PAS, Sirius red and histopathological scoring. Dasatinib attenuated renal cortical mRNA expression for SREBP1, iNOS, PDGFA and TGFβ and IHC staining for CD68, ASMA and SQSTM1/P62 and WB for caspase-3 and SQSTM1/P62, while elevating LC3 expression. Moreover, Dasatinib ameliorated ORC; glomerulosclerosis, glomerular expansion, tubular dilatation, vacuolation and casts; inflammatory cellular infiltration; and fibrosis. Dasatinib is a promising therapy for ORC by correcting autophagy impairment, attenuating lipogenesis, apoptosis and macrophage infiltration by inducing antifibrotic activity.
    Keywords:  Dasatinib; autophagy; macrophages; obesity; tyrosine kinase inhibitors
    DOI:  https://doi.org/10.3390/cells11040746
  12. Exp Gerontol. 2022 Feb 16. pii: S0531-5565(22)00052-3. [Epub ahead of print]162 111744
    Serum irisin level is independent of sarcopenia and related muscle parameters in older adults.
    Ji Yeon Baek, Il-Young Jang, Hee-Won Jung, So Jeong Park, Jin Young Lee, Eunah Choi, Yun Sun Lee, Eunju Lee, Beom-Jun Kim.
       BACKGROUND: Accumulating evidence indicates that irisin, a myokine consisting of 112 amino acids, protects against muscle wasting in an autocrine manner; however, its impact on human muscle metabolism is still inconclusive. In this cross-sectional study, we aimed to investigate whether circulating irisin could be a potential biomarker reflecting muscle health in older adults.
    METHODS: Comprehensive assessment of muscle mass; muscle function, including grip strength, gait speed, chair stand test, and short physical performance battery (SPPB); and muscle quality was performed in 143 older adults who visited outpatient geriatrics and endocrinology clinics. Sarcopenia was defined using the Asian-specific cutoff value. Blood samples were also collected to determine serum irisin concentration which was measured using enzyme immunoassay.
    RESULTS: The serum irisin level was not significantly different according to the status of sarcopenia, low muscle mass, weak muscle strength, poor physical performance, and poor muscle quality, before or after adjustment for age, sex, appendicular skeletal muscle (ASM), and body mass index. Consistently, the association of circulating irisin level with sarcopenia-related parameters (skeletal muscle index, grip strength, gait speed, chair stand test, SPPB, and grip strength/body weight or ASM) was not evident in any adjustment models.
    CONCLUSIONS: Despite the clear implication of irisin's involvement in muscle metabolism based on experimental research, we did not observe a definite association between its serum level and clinical muscle parameters in humans. These results suggest that the blood irisin level may not accurately predict the risk of sarcopenia in older adults.
    Keywords:  Aging; Biomarker; Irisin; Myokine; Older adults; Sarcopenia
    DOI:  https://doi.org/10.1016/j.exger.2022.111744
  13. BMC Nephrol. 2022 Feb 22. 23(1): 75
    Clinical practice guideline exercise and lifestyle in chronic kidney disease.
    Luke A Baker, Daniel S March, Thomas J Wilkinson, Roseanne E Billany, Nicolette C Bishop, Ellen M Castle, Joseph Chilcot, Mark D Davies, Matthew P M Graham-Brown, Sharlene A Greenwood, Naushad A Junglee, Archontissa M Kanavaki, Courtney J Lightfoot, Jamie H Macdonald, Gabriella M K Rossetti, Alice C Smith, James O Burton.
      
    DOI:  https://doi.org/10.1186/s12882-021-02618-1
  14. BMC Nephrol. 2022 02 21. 23(1): 72
    Gait disorders in CKD patients: muscle wasting or cognitive impairment? A cross-sectional pilot study to investigate gait signatures in Stage 1-5 CKD patients.
    Damiano D Zemp, Olivier Giannini, Pierluigi Quadri, Marco Rabuffetti, Mauro Tettamanti, Eling D de Bruin.
       BACKGROUND: Instrumental gait analysis in nephrology is widely neglected, although patients with chronic kidney disease (CKD) show brain changes due to cerebrovascular disease and metabolic disorders that can potentially influence gait quality. Our study assesses the association between CKD stages and gait parameters, to understand the prevalent status of brain related gait parameters (i.e. variability) and of performance related parameters (i.e. gait speed, stride length). We hypothesize that gait changes are detectable already in early stages of CKD.
    METHODS: Forty-five participants distributed in 5 CKD severity groups underwent an instrumental gait analysis via a triaxial accelerometer affixed to the lower trunk under single- and dual-task conditions. In addition to spatio-temporal parameters, variability and dual-task cost of gait were extracted. A battery of clinical assessments was conducted with the aim of helping to better explain the findings of the gait analysis. A correlation analysis was made to investigate a linear relation between gait parameters and CKD severity.
    RESULTS: Statistically significant correlations (Pearson correlation coefficient) with CKD severity were found for gait speed (p < 0.01, r = -0.55, 95% CI [-0.73;-0.30]), stride length ( p < 0.01, r = -0.40, 95% CI [-0.62;-0.12]), step length (p < 0.01, r = -0.41, 95% CI [-0.63;-0.13], coefficient of variance (CV) of step length (p = 0.01, r = 0.36, 95% CI [0.08;0.59]), gait regularity (p < 0.01, r = -0.38, 95% CI [-0.61;-0.10]), dual-task cost of gait speed (p < 0.01, r = 0.40, 95% CI [0.13;0.62]) and dual-task cost of stride time (p = 0.03, r = 0.32, 95% CI [0.03;0.57]). Adjustment for age and gender confirmed all results except for gait regularity. With increasing severity of renal failure, Handgrip strength, Time for the Expanded Timed Get Up and Go test, executive functions, haemoglobin, and haematocrit, worsen.
    CONCLUSIONS: The correlation of CKD severity with spatio-temporal parameters (performance indices mainly relatable to peripheral functionality) and with variability of gait (related to central factors) supported by the results of the clinical assessments, suggests that gait disturbance in CKD patients is not only due to metabolic factors that lead to muscle wasting, but also to brain changes that affect motor control. This suggests that the treatment of renal disease should include cognitive aspects in addition to metabolic and functional factors.
    Keywords:  Chronic kidney disease; Cognitive impairment; Functional decline; Gait disorders; Gait variability; Sarcopenia
    DOI:  https://doi.org/10.1186/s12882-022-02697-8
  15. Nutrients. 2022 Feb 14. pii: 799. [Epub ahead of print]14(4):
    The Panax ginseng Berry Extract and Soluble Whey Protein Hydrolysate Mixture Ameliorates Sarcopenia-Related Muscular Deterioration in Aged Mice.
    Min-Ji Han, Seok-Jun Park, Sang-Jun Lee, Se-Young Choung.
      Sarcopenia is prevalent as the aging population grows. Therefore, the need for supplements for the elderly is increasing. This study aimed to investigate the efficacy and mechanism of a Panax ginseng berry extract (GBE) and soluble whey protein hydrolysate (WPH) mixture on a sarcopenia-related muscular deterioration in aged mice. Ten-month-old male C57BL/6J mice were administered three different doses of the GBE + WPH mixture for 8 weeks; 700 mg/kg, 900 mg/kg, and 1100 mg/kg. Grip strength, serum inflammatory cytokines level, and mass of muscle tissues were estimated. The deteriorating function of aging muscle was investigated via protein or gene expression. Grip strength and mass of three muscle tissues were increased significantly in a dose-dependent manner, and increased anti-inflammatory cytokine alleviated systemic inflammatory state. The mixture resolved the imbalance of muscle protein turnover through activation of the PI3K/Akt pathway and increased gene expression of the muscle regeneration-related factors, while decreasing myostatin, which interferes with muscle protein synthesis and regeneration. Furthermore, we confirmed that increased mitochondria number in muscle with the improvement of mitochondrial biogenesis. These physiological changes were similar to the effects of exercise.
    Keywords:  Panax ginseng berry extract; aging; muscular deterioration; protein turnover; sarcopenia; skeletal muscle; soluble whey protein hydrolysate
    DOI:  https://doi.org/10.3390/nu14040799
  16. Clin Kidney J. 2022 Mar;15(3): 553-559
    Application of the Clinical Frailty Score and body composition and upper arm strength in haemodialysis patients.
    Andrew Davenport.
       Background: To improve outcomes, simple screening tests are required to detect patients at increased risk of mortality. As patients with muscle weakness and wasting are at increased risk of death, we wished to review the use of the Clinical Frailty Score (CFS).
    Patients and methods: Dialysis staff graded haemodialysis (HD) patients attending for routine outpatient sessions using the CFS, a functional scoring scale, for patients who require help with their instrumental activities of daily living, classified as clinically frail with scores >4, which were compared with contemporaneous Stoke-Davies comorbidity scores, post-HD body composition measured by bioimpedance, hand grip strength (HGS) and standard laboratory investigations.
    Results: The results from 2089 patients (60.2% male) were reviewed, with 890 (42.6%) classified as frail. Frail patients were older [mean ± standard deviation (SD) 71.5 ± 15.6 versus 59.1 ± 15.6 years) and female (50.7% versus 37.3%) and had greater comorbidity {median 2 [interquartile range (IQR) 1-3] versus 1 [0-2]}, body mass index (BMI) (26.0 ± 6.7 versus 25.5 ± 5.4 kg/m2),  C-reactive protein (CRP) [8 (IQR 3-20) versus 5 (2-11) mg/L], lower serum albumin (37.6 ± 4.7 versus 40.1 ± 4.7 g/L),  lean BMI (8.9 ± 1.7 versus 9.7 ± 1.6 kg/m2) and HGS [13.4 (IQR 9.6-18.8) versus 20.9 (14.5-29) kg] (all P < 0.001). Frailty was independently associated in a multivariable logistic model with age {odds ratio [OR] 2.33 [95% confidence limit (CL) 2.01-2.7]}, body fat mass [OR 1.02 (CL 1.01-1.03)], log CRP [OR 1.63 (CL 1.28-2.07)] (all P < 0.001) and comorbidity [OR 1.45 (CL 1.17-1.8); P = 0.001] and negatively associated with albumin [OR 0.95 (CL 0.92-0.98) and HGS [OR 0.91 (CL 0.9-0.93)] (both P < 0.001).
    Conclusion: Frail patients are at increased risk of mortality and, as such, simple reliable screening tools are required to rapidly detect patients at risk. The CFS is a useful screening tool that can be readily performed by dialysis staff to identify frail patients. Frailty in HD patients was associated with increasing age, comorbidity, fat weight and inflammation and reduced muscle strength and muscle mass. There is an overlap between frailty and both sarcopenia and protein energy wasting, which requires additional assessments, potentially including body composition, strength, dietary assessments and laboratory investigations. In addition, as the CFS offers a scale, patient trajectories can potentially be serially monitored over time, thus allowing patient-specific interventions or holistic care plans.
    Keywords:  bioimpedance; body mass index; co-morbidity; frailty; haemodialysis; hand grip strength; muscle mass
    DOI:  https://doi.org/10.1093/ckj/sfab228
  17. PeerJ. 2022 ;10 e12878
    Autophagy-related prognostic signature for survival prediction of triple negative breast cancer.
    Qiong Yang, Kewang Sun, Wenjie Xia, Ying Li, Miaochun Zhong, Kefeng Lei.
       Background: Triple-negative breast cancer (TNBC) is a highly aggressive type of cancer with few available treatment methods. The aim of the current study was to provide a prognostic autophagy-related gene (ARG) model to predict the outcomes for TNBC patients using bioinformatic analysis.
    Methods: mRNA expression data and its clinical information for TNBC samples obtained from The Cancer Genome Atlas (TCGA) and Metabric databases were extracted for bioinformatic analysis. Differentially expressed autophagy genes were identified using the Wilcoxon rank sum test in R software. ARGs were downloaded from the Human Autophagy Database. The Kaplan-Meier plotter was employed to determine the prognostic significance of the ARGs. The sample splitting method and Cox regression analysis were employed to establish the risk model and to demonstrate the association between the ARGs and the survival duration. The corresponding ARG-transcription factor interaction network was visualized using the Cytoscape software.
    Results: A signature-based risk score model was established for eight genes (ITGA3, HSPA8, CTSD, ATG12, CLN3, ATG7, MAP1LC3C, and WIPI1) using the TCGA data and the model was validated with the GSE38959 and Metabric datasets, respectively. Patients with high risk scores had worse survival outcomes than those with low risk scores. Of note, amplification of ATG12 and reduction of WIPI were confirmed to be significantly correlated with the clinical stage of TNBC.
    Conclusion: An eight-gene autophagic signature model was developed in this study to predict the survival risk for TNBC. The genes identified in the study may favor the design of target agents for autophagy control in advanced TNBC.
    Keywords:  Autophagy gene; Predict model; Prognosis; TCGA; Triple negative breast cancer
    DOI:  https://doi.org/10.7717/peerj.12878
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