bims-aucach Biomed News
on Autophagy and cachexia
Issue of 2022–01–23
nine papers selected by
Kleiton Silva, Rowan University
  1. Development of ovarian tumour causes significant loss of muscle and adipose tissue: a novel mouse model for cancer cachexia study.
  2. Effect of Rehabilitation Nutrition Care Process on Physical Function in Lung Cancer Cachexia: A Case Report.
  3. Nutritional Approach to Cancer Cachexia: A Proposal for Dietitians.
  4. Impact of Cancer Cachexia on Cardiac and Skeletal Muscle: Role of Exercise Training.
  5. The critical role of STAT3 in biogenesis of tumor-derived exosomes with potency of inducing cancer cachexia in vitro and in vivo.
  6. Chronic Kidney Disease-Associated Pruritus: A Glance at Novel and Lesser-Known Treatments.
  7. Weight Loss in Advanced Cancer: Sex Differences in Health-Related Quality of Life and Body Image.
  8. Blocking autophagy overcomes resistance to dual histone deacetylase and proteasome inhibition in gynecologic cancer.
  9. Automated cross-sectional analysis of trained, severely atrophied and recovering rat skeletal muscles using MyoVision 2.0.
  1. J Cachexia Sarcopenia Muscle. 2022 Jan 19.
    Development of ovarian tumour causes significant loss of muscle and adipose tissue: a novel mouse model for cancer cachexia study.
    Yi Luan, Yaqi Zhang, Seok-Yeong Yu, Mikyoung You, Pauline C Xu, Soonkyu Chung, Takeshi Kurita, Jie Zhu, So-Youn Kim.
       BACKGROUND: Cancer-associated cachexia (CAC) is a complex syndrome of progressive muscle wasting and adipose loss with metabolic dysfunction, severely increasing the morbidity and mortality risk in cancer patients. However, there are limited studies focused on the underlying mechanisms of the progression of CAC due to the complexity of this syndrome and the lack of preclinical models that mimics its stagewise progression.
    METHODS: We characterized the initiation and progression of CAC in transgenic female mice with ovarian tumours. We measured proposed CAC biomarkers (activin A, GDF15, IL-6, IL-1β, and TNF-α) in sera (n = 6) of this mouse model. The changes of activin A and GDF15 (n = 6) were correlated with the decline of bodyweight over time. Morphometry and signalling markers of muscle atrophy (n ≥ 6) and adipose tissue wasting (n ≥ 7) were assessed during CAC progression.
    RESULTS: Cancer-associated cachexia symptoms of the transgenic mice model used in this study mimic the progression of CAC seen in humans, including drastic body weight loss, skeletal muscle atrophy, and adipose tissue wasting. Serum levels of two cachexia biomarkers, activin A and GDF15, increased significantly during cachexia progression (76-folds and 10-folds, respectively). Overactivation of proteolytic activity was detected in skeletal muscle through up-regulating muscle-specific E3 ligases Atrogin-1 and Murf-1 (16-folds and 14-folds, respectively) with decreasing cross-sectional area of muscle fibres (P < 0.001). Muscle wasting mechanisms related with p-p38 MAPK, FOXO3, and p-AMPKα were highly activated in concurrence with an elevation in serum activin A. Dramatic fat loss was also observed in this mouse model with decreased fat mass (n ≥ 6) and white adipocytes sizes (n = 6) (P < 0.0001). The adipose tissue wasting was based on thermogenesis, supported by the up-regulation of uncoupling protein 1 (UCP1). Fibrosis in adipose tissue was also observed in concurrence with adipose tissue loss (n ≥ 13) (p < 0.0001).
    CONCLUSIONS: Our novel preclinical CAC mouse model mimics human CAC phenotypes and serum biomarkers. The mouse model in this study showed proteolysis in muscle atrophy, browning in adipose tissue wasting, elevation of serum activin A and GDF15, and atrophy of pancreas and liver. This mouse line would be the best preclinical model to aid in clarifying molecular mediators of CAC and dissecting metabolic dysfunction and tissue atrophy during the progression of CAC.
    Keywords:  Activin A; Adipose; Cancer cachexia; Mouse model; Muscle; Ovarian tumour
    DOI:  https://doi.org/10.1002/jcsm.12864
  2. Phys Ther Res. 2021 ;24(3): 291-294
    Effect of Rehabilitation Nutrition Care Process on Physical Function in Lung Cancer Cachexia: A Case Report.
    Kengo Shirado, Shota Okuno, Toshihiro Yamashita.
       OBJECTIVES: Patients with cancer cachexia have poor adherence to treatment, which affects their prognosis. Currently, there are many studies on the effects of rehabilitation on cancer cachexia, but there is a lack of evidence on the effects of nutrition therapy alone or in combination with rehabilitation and nutrition therapy. This article describes a case in which rehabilitation nutrition care process was effective in a patient with lung cancer who developed cancer cachexia.
    METHODS: A 68-year-old woman was hospitalized for treatment of lung adenocarcinoma. The patient had moderate malnutrition, sarcopenia, and cachexia at the time of admission, so the authors intervened according to rehabilitation nutrition care process. The physiotherapist mainly prescribed resistance training and aerobic exercise, 40-60 minutes a day, 5-6 days a week. And the dietitian provided oral nutritional supplements (100 kcal, branched-chain amino acid: 3.0 g) in addition to hospital food and adjusted the patient's energy intake to 26.96-33.05 kcal/kg/day and protein intake to 1.07-1.14 g/kg/day.
    OUTCOMES: Comparing the initial evaluation with the discharge, nutritional status, such as body mass index and skeletal muscle mass, and physical functions, such as maximum grip strength, gait speed, and functional independence measure (motor items), were improved.
    CONCLUSIONS: Rehabilitation nutrition care process-based interventions may improve nutritional status and physical functions more than exercise therapy alone in patients with lung cancer cachexia.
    Keywords:  Case report; Exercise; Lung neoplasms; Malnutrition; Nutrition therapy
    DOI:  https://doi.org/10.1298/ptr.E10112
  3. Nutrients. 2022 Jan 14. pii: 345. [Epub ahead of print]14(2):
    Nutritional Approach to Cancer Cachexia: A Proposal for Dietitians.
    Kotone Tanaka, Sho Nakamura, Hiroto Narimatsu.
      Cachexia is one of the most common, related factors of malnutrition in cancer patients. Cancer cachexia is a multifactorial syndrome characterized by persistent loss of skeletal muscle mass and fat mass, resulting in irreversible and progressive functional impairment. The skeletal muscle loss cannot be reversed by conventional nutritional support, and a combination of anti-inflammatory agents and other nutrients is recommended. In this review, we reviewed the effects of nutrients that are expected to combat muscle loss caused by cancer cachexia (eicosapentaenoic acid, β-hydroxy-β-methylbutyrate, creatine, and carnitine) to propose nutritional approaches that can be taken at present. Current evidence is based on the intake of nutrients as supplements; however, the long-term and continuous intake of nutrients as food has the potential to be useful for the body. Therefore, in addition to conventional nutritional support, we believe that it is important for the dietitian to work with the clinical team to first fully assess the patient's condition and then to safely incorporate nutrients that are expected to have specific functions for cancer cachexia from foods and supplements.
    Keywords:  EPA; HMB; cachexia; cancer; carnitine; creatine
    DOI:  https://doi.org/10.3390/nu14020345
  4. Cancers (Basel). 2022 Jan 11. pii: 342. [Epub ahead of print]14(2):
    Impact of Cancer Cachexia on Cardiac and Skeletal Muscle: Role of Exercise Training.
    Cláudia Bordignon, Bethânia S Dos Santos, Daniela D Rosa.
      Cachexia is a multifactorial syndrome that presents with, among other characteristics, progressive loss of muscle mass and anti-cardiac remodeling effect that may lead to heart failure. This condition affects about 80% of patients with advanced cancer and contributes to worsening patients' tolerance to anticancer treatments and to their premature death. Its pathogenesis involves an imbalance in metabolic homeostasis, with increased catabolism and inflammatory cytokines levels, leading to proteolysis and lipolysis, with insufficient food intake. A multimodal approach is indicated for patients with cachexia, with the aim of reducing the speed of muscle wasting and improving their quality of life, which may include nutritional, physical, pharmacologic, and psychological support. This review aims to outline the mechanisms of muscle loss, as well as to evaluate the current clinical evidence of the use of physical exercise in patients with cachexia.
    Keywords:  cancer cachexia; cardiac muscle wasting; muscle wasting; physical exercise
    DOI:  https://doi.org/10.3390/cancers14020342
  5. Oncogene. 2022 Jan 16.
    The critical role of STAT3 in biogenesis of tumor-derived exosomes with potency of inducing cancer cachexia in vitro and in vivo.
    Meng Fan, Weikuan Sun, Xiaofan Gu, Shanshan Lu, Qiang Shen, Xuan Liu, Xiongwen Zhang.
      Tumor-derived exosomes are emerging mediators of cancer cachexia. Clarifying the regulation of exosome biogenesis and finding possible targets for cancer cachexia therapy are important and necessary. In the present study, systemic analysis of the roles of STAT3 in controlling exosome biogenesis of murine C26 colon tumor cells and its contribution to the development of cancer cachexia is conducted. The genetic manipulation of STAT3 expression, STAT3 knockout (KO) or overexpression (OE), significantly affected the exosome biogenesis and also the potency of C26 conditioned medium (CM) in inducing muscle atrophy and lipolysis in vitro. The genetic manipulation of STAT3 expression caused change in phosphorylation of PKM2 and glycolysis. PKM2/SNAP23 pathway was involved in regulation of exosome biogenesis by STAT3 genetic manipulation as well as by STAT3 inhibitors in C26 cells. Mice inoculated with STAT3 knockout or overexpression C26 cells exhibited ameliorated or aggravated cancer cachexia symptoms, with a positive correlation with the serum exosome and IL-6 levels. The STAT3/PKM2/SNAP23 pathway was affected in C26 tumor tissues with genetic manipulation of STAT3 expression. The capacity of exosome biogenesis of different human cancer cells also exhibited a positive correlation with the activation of STAT3/PKM2/SNAP23 pathway. The research presented here confirms that STAT3 plays a critical role in regulating biogenesis of tumor-derived exosomes which could contribute to cancer cachexia development.
    DOI:  https://doi.org/10.1038/s41388-021-02151-3
  6. Cureus. 2022 Jan;14(1): e21127
    Chronic Kidney Disease-Associated Pruritus: A Glance at Novel and Lesser-Known Treatments.
    Sayed Elhag, Nancy Rivas, Sreedevi Tejovath, Nadiah Mustaffa, Nadira Deonarine, Muzaffar Abdullah Hashmi, Sindhura Yerneni, Pousette Hamid.
      Chronic kidney disease-associated pruritus (CKD-aP), also known as uremic pruritus, has been associated with increased mortality and lower quality of life among patients with chronic kidney disease (CKD). The relentless nature of the condition is mainly due to its diverse and complex etiologies, which are still being studied. Despite the introduction of many agents to treat it, the resolution rates of CKD-aP still remain unsatisfactory. This study sought to review the lesser-known/novel treatments and establish a relationship between their mechanism of action and the proposed etiologies implicated in CKD-aP. We also discuss the role of dialysis modification in managing CKD-aP. A decent proportion of the reviewed studies have proposed that the agents analyzed in them act through hampering inflammation. Interestingly, the results of two agents alluded to the role of dysbiosis in CKD-aP. The addition of hemoperfusion to the dialysis regimen of patients with CKD-aP improved the severity of their symptoms. The featured treatments could be tried in patients with intractable symptoms. However, additional research is needed to confirm the findings reported in these studies. A better understanding of the pathologic mechanisms is required to help guide the development of agents that can better treat CKD-aP.
    Keywords:  ckd; ckd pruritus; dialysis; hemoperfusion; itching; uremic pruritus
    DOI:  https://doi.org/10.7759/cureus.21127
  7. Life (Basel). 2022 Jan 12. pii: 105. [Epub ahead of print]12(1):
    Weight Loss in Advanced Cancer: Sex Differences in Health-Related Quality of Life and Body Image.
    Charlotte Goodrose-Flores, Helén Eke, Stephanie E Bonn, Linda Björkhem-Bergman, Ylva Trolle Lagerros.
      Weight maintenance is a priority in cancer care, but weight loss is common and a serious concern. This study explores if there are sex differences in the perception of weight loss and its association to health-related quality of life (HRQoL) and body image. Cancer patients admitted to Advanced Medical Home Care were recruited to answer a questionnaire, including characteristics, the HRQoL-questionnaire RAND-36, and a short form of the Body Image Scale. Linear regression analyses stratified by sex and adjusted for age were performed to examine associations between percent weight loss and separate domains of HRQoL and body image score in men and women separately. In total, 99 participants were enrolled, of which 80 had lost weight since diagnosis. In men, an inverse association between weight loss and the HRQoL-domain physical functioning, β = -1.34 (95%CI: -2.44, -0.24), and a positive association with body image distress, β = 0.22 (95%CI: 0.07, 0.37), were found. In women, weight loss was associated with improvement in the HRQoL-domain role limitations due to physical health, β = 2.02 (95%CI: 0.63, 3.41). Following a cancer diagnosis, men appear to experience weight loss more negatively than women do. Recognizing different perceptions of weight loss may be of importance in clinical practice.
    Keywords:  body image; cancer; health-related quality of life; palliative; sex differences; weight loss
    DOI:  https://doi.org/10.3390/life12010105
  8. Cell Death Dis. 2022 Jan 17. 13(1): 59
    Blocking autophagy overcomes resistance to dual histone deacetylase and proteasome inhibition in gynecologic cancer.
    Jianling Bi, Yuping Zhang, Paige K Malmrose, Haley A Losh, Andreea M Newtson, Eric J Devor, Kristina W Thiel, Kimberly K Leslie.
      Histone deacetylase (HDAC) inhibitors and proteasome inhibitors have been approved by the FDA for the treatment of multiple myeloma and lymphoma, respectively, but have not achieved similar activity as single agents in solid tumors. Preclinical studies have demonstrated the activity of the combination of an HDAC inhibitor and a proteasome inhibitor in a variety of tumor models. However, the mechanisms underlying sensitivity and resistance to this combination are not well-understood. This study explores the role of autophagy in adaptive resistance to dual HDAC and proteasome inhibition. Studies focus on ovarian and endometrial gynecologic cancers, two diseases with high mortality and a need for novel treatment approaches. We found that nanomolar concentrations of the proteasome inhibitor ixazomib and HDAC inhibitor romidepsin synergistically induce cell death in the majority of gynecologic cancer cells and patient-derived organoid (PDO) models created using endometrial and ovarian patient tumor tissue. However, some models were not sensitive to this combination, and mechanistic studies implicated autophagy as the main mediator of cell survival in the context of dual HDAC and proteasome inhibition. Whereas the combination of ixazomib and romidepsin reduces autophagy in sensitive gynecologic cancer models, autophagy is induced following drug treatment of resistant cells. Pharmacologic or genetic inhibition of autophagy in resistant cells reverses drug resistance as evidenced by an enhanced anti-tumor response both in vitro and in vivo. Taken together, our findings demonstrate a role for autophagic-mediated cell survival in proteasome inhibitor and HDAC inhibitor-resistant gynecologic cancer cells. These data reveal a new approach to overcome drug resistance by inhibiting the autophagy pathway.
    DOI:  https://doi.org/10.1038/s41419-022-04508-2
  9. J Appl Physiol (1985). 2022 Jan 20.
    Automated cross-sectional analysis of trained, severely atrophied and recovering rat skeletal muscles using MyoVision 2.0.
    Mark Robert Viggars, Yuan Wen, Charlotte A Peterson, Jonathan C Jarvis.
      The number of myonuclei within a muscle fiber is an important factor in muscle growth, but its regulation during muscle adaptation is not well understood. We aimed to elucidate the timecourse of myonuclear dynamics during endurance training, loaded and concentric resistance training, and nerve silencing-induced disuse atrophy with subsequent recovery. We modified tibialis anterior muscle activity in free-living rats with electrical stimulation from implantable pulse generators, or with implantable osmotic pumps delivering tetrodotoxin (TTX) to silence the motor nerve without transection. We used the updated, automated software MyoVision to measure fiber type-specific responses in whole tibialis anterior cross-sections (~8000 fibers each). Seven days of continuous low frequency stimulation (CLFS) reduced muscle mass (-12%), increased slower myosin isoforms and reduced IIX/IIB fibers (-32%) and substantially increased myonuclei especially in IIX/IIB fibers (55.5%). High load resistance training (Spillover), produced greater hypertrophy (~16%) in muscle mass and fiber cross-sectional area (CSA) than low load resistance training (concentric, ~6%) and was associated with myonuclear addition in all fiber types (35-46%). TTX-induced nerve silencing resulted in progressive loss in muscle mass, fiber CSA, and myonuclei per fiber cross-section (-50.7%, -53.7%, -40.7%, respectively at 14 days). Myonuclear loss occurred in a fiber type-independent manner, but subsequent recovery during voluntary habitual activity suggested that type IIX/IIB fibers contained more new myonuclei during recovery from severe atrophy. This study demonstrates the power and accuracy provided by the updated MyoVision software and introduces new models for studying myonuclear dynamics in training, detraining, retraining, repeated disuse, and recovery.
    Keywords:  Atrophy; Hypertrophy; Image Analysis; Myonuclei; Skeletal Muscle
    DOI:  https://doi.org/10.1152/japplphysiol.00491.2021
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