bims-aucach 2021-12-26 papers

bims-aucach

Biomed News

on Autophagy and cachexia

Issue of 2021‒12‒26
eighteen papers selected by
Kleiton Silva
Rowan University

Skeletal muscle mitochondrial dysfunction and muscle and whole-body functional deficits in cancer patients with weight loss.
Mitochondrial Bioenergetic and Proteomic Phenotyping Reveals Organ-Specific Consequences of Chronic Kidney Disease in Mice.
Bile Acid Dysregulation Is Intrinsically Related to Cachexia in Tumor-Bearing Mice.
Emerging role of mitophagy in myoblast differentiation and skeletal muscle remodeling.
Extracellular vesicles derived from tumour cells as a trigger of energy crisis in the skeletal muscle.
The Implication of Autophagy in Gastric Cancer Progression.
MicroRNAs as Potential Biomarkers for Exercise-Based Cancer Rehabilitation in Cancer Survivors.
Oxidative Stress in ICU Patients: ROS as Mortality Long-Term Predictor.
Weight Loss in Cancer Patients Correlates With p38β MAPK Activation in Skeletal Muscle.
Pardaxin Activates Excessive Mitophagy and Mitochondria-Mediated Apoptosis in Human Ovarian Cancer by Inducing Reactive Oxygen Species.
Overexpression of NDUFV1 alleviates renal damage by improving mitochondrial function in unilateral ureteral obstruction model mice.
Muscle adaptation to sleeve gastrectomy: Potential role of nutritional supplementation and physical exercise.
Differential Effects of 25-Hydroxyvitamin D3 versus 1α 25-Dihydroxyvitamin D3 on Adipose Tissue Browning in CKD-Associated Cachexia.
Decreased miR-497-5p Suppresses IL-6 Induced Atrophy in Muscle Cells.
The contributory role of vascular health in age-related anabolic resistance.
Neurobiology of cancer: Definition, historical overview, and clinical implications.
Targeting Mitochondrial OXPHOS and Their Regulatory Signals in Prostate Cancers.
LPS induces rapid increase in GDF15 levels in mice, rats and humans but is not required for anorexia in mice.

J Appl Physiol (1985). 2021 Dec 23.

Skeletal muscle mitochondrial dysfunction and muscle and whole-body functional deficits in cancer patients with weight loss.

Hawley E Kunz, John D Port, Kenton R Kaufman, Aminah Jatoi, Corey R Hart, Kevin J Gries, Ian R Lanza, Rajiv Kumar.

  Reductions in skeletal muscle mass and function are often reported in patients with cancer-associated weight loss and are associated with reduced quality of life, impaired treatment tolerance, and increased mortality. Although cellular changes, including altered mitochondrial function, have been reported in animals, such changes have been incompletely characterized in humans with cancer. Whole body and skeletal muscle physical function, skeletal muscle mitochondrial function and whole-body protein turnover were assessed in 8 patients with cancer-associated weight loss (10.1±4.2% body weight over 6-12 months) and 19 age-, sex-, and BMI-matched healthy controls to characterize skeletal muscle changes at the whole body, muscle, and cellular level. Potential pathways involved in cancer-induced alterations in metabolism and mitochondrial function were explored by interrogating skeletal muscle and plasma metabolomes. Despite similar lean mass compared to control participants, patients with cancer exhibited reduced habitual physical activity (57% fewer daily steps), cardiorespiratory fitness (22% lower VO2peak [mL/kg/min]) and leg strength (35% lower isokinetic knee extensor strength) and greater leg neuromuscular fatigue (36% greater decline in knee extensor torque). Concomitant with these functional declines, patients with cancer had lower mitochondrial oxidative capacity (25% lower State 3 O2 flux [pmol/s/mg tissue]) and ATP production (23% lower State 3 ATP production [pmol/s/mg tissue]) and alterations in phospholipid metabolite profiles indicative of mitochondrial abnormalities. Whole body protein turnover was unchanged. These findings demonstrate mitochondrial abnormalities concomitant with whole-body and skeletal muscle functional derangements associated with human cancer, supporting future work studying the role of mitochondria in the muscle deficits associated with cancer.

Keywords:  cancer-associated weight loss; mitochondria; muscle strength; physical activity; skeletal muscle

DOI:  https://doi.org/10.1152/japplphysiol.00746.2021
Cells. 2021 Nov 24. pii: 3282. [Epub ahead of print]10(12):

Mitochondrial Bioenergetic and Proteomic Phenotyping Reveals Organ-Specific Consequences of Chronic Kidney Disease in Mice.

Trace Thome, Madeline D Coleman, Terence E Ryan.

  Chronic kidney disease (CKD) results in reduced kidney function, uremia, and accumulation of uremic metabolites. Mitochondrial alterations have been suggested to play a role in the disease pathology within various tissues. The purpose of this study was to perform a comprehensive bioenergetic and proteomic phenotyping of mitochondria from skeletal muscle (SkM), cardiac muscle (CM), and renal tissue from mice with CKD. The 5-month-old C57BL/6J male mice were fed a casein control or adenine-supplemented diet for 6 months. CKD was confirmed by blood urea nitrogen. A mitochondrial diagnostic workflow was employed to examine respiratory function, membrane and redox potential, reactive oxygen species production, and maximal activities of matrix dehydrogenases and electron transport system (ETS) protein complexes. Additionally, tandem-mass-tag-assisted proteomic analyses were performed to uncover possible differences in mitochondrial protein abundance. CKD negatively impacted mitochondrial energy transduction (all p < 0.05) in SkM, CM, and renal mitochondria, when assessed at physiologically relevant cellular energy demands (ΔGATP) and revealed the tissue-specific impact of CKD on mitochondrial health. Proteomic analyses indicated significant abundance changes in CM and renal mitochondria (115 and 164 proteins, p < 0.05), but no differences in SkM. Taken together, these findings reveal the tissue-specific impact of chronic renal insufficiency on mitochondrial health.

Keywords:  CKD; bioenergetics; cardiac; kidney; mitochondria; muscle; proteomics

DOI:  https://doi.org/10.3390/cells10123282
Cancers (Basel). 2021 Dec 20. pii: 6389. [Epub ahead of print]13(24):

Bile Acid Dysregulation Is Intrinsically Related to Cachexia in Tumor-Bearing Mice.

Morgane M Thibaut, Justine Gillard, Adeline Dolly, Martin Roumain, Isabelle A Leclercq, Nathalie M Delzenne, Giulio G Muccioli, Laure B Bindels.

  Bile acids exert diverse actions on host metabolism and immunity through bile acid-activated receptors, including Takeda G protein-coupled receptor 5 (TGR5). We have recently evidenced an alteration in bile acids in cancer cachexia, an inflammatory and metabolic syndrome contributing to cancer death. This current study aims to further explore the links emerging between bile acids and cancer cachexia. First, we showed that bile flow is reduced in cachectic mice. Next, comparing mice inoculated with cachexia-inducing and with non-cachexia-inducing C26 colon carcinoma cells, we demonstrated that alterations in the bile acid pathways and profile are directly associated with cachexia. Finally, we performed an interventional study using ursodeoxycholic acid (UDCA), a compound commonly used in hepatobiliary disorders, to induce bile acid secretion and decrease inflammation. We found that UDCA does not improve hepatic inflammation and worsens muscle atrophy in cachectic mice. This exacerbation of the cachectic phenotype upon UDCA was accompanied by a decreased TGR5 activity, suggesting that TGR5 agonists, known to reduce inflammation in several pathological conditions, could potentially counteract cachectic features. This work brings to light major evidence sustaining the emerging links between bile acids and cancer cachexia and reinforces the interest in studying bile acid-activated receptors in this context.

Keywords:  G protein-coupled bile acid receptor; GPBAR1; NC26; TGR5; TGR5 cell reporter assay; bile flow; hepatic inflammation; muscle atrophy; non-cachectic C26 mice; ursodeoxycholic acid

DOI:  https://doi.org/10.3390/cancers13246389
Semin Cell Dev Biol. 2021 Dec 16. pii: S1084-9521(21)00308-6. [Epub ahead of print]

Emerging role of mitophagy in myoblast differentiation and skeletal muscle remodeling.

Fasih Ahmad Rahman, Joe Quadrilatero.

  Mitochondrial turnover in the form of mitophagy is emerging as a central process in maintaining cellular function. The degradation of damaged mitochondria through mitophagy is particularly important in cells/tissues that exhibit high energy demands. Skeletal muscle is one such tissue that requires precise turnover of mitochondria in several conditions in order to optimize energy production and prevent bioenergetic crisis. For instance, the formation of skeletal muscle (i.e., myogenesis) is accompanied by robust turnover of low-functioning mitochondria to eventually allow the formation of high-functioning mitochondria. In mature skeletal muscle, alterations in mitophagy-related signaling occur during exercise, aging, and various disease states. Nonetheless, several questions regarding the direct role of mitophagy in various skeletal muscle conditions remain unknown. Furthermore, given the heterogenous nature of skeletal muscle with respect to various cellular and molecular properties, and the plasticity in these properties in various conditions, the involvement and characterization of mitophagy requires more careful consideration in this tissue. Therefore, this review will highlight the known mechanisms of mitophagy in skeletal muscle, and discuss their involvement during myogenesis and various skeletal muscle conditions. This review also provides important considerations for the accurate measurement of mitophagy and interpretation of data in skeletal muscle.

Keywords:  Aging; Atrophy; Autophagy; Cancer; Differentiation; Fiber type; Mitochondria; Mitochondrial network; Mitophagy; Myoblasts; Myogenesis; Regeneration; Remodeling; Skeletal muscle

DOI:  https://doi.org/10.1016/j.semcdb.2021.11.026
J Cachexia Sarcopenia Muscle. 2021 Dec 20.

Extracellular vesicles derived from tumour cells as a trigger of energy crisis in the skeletal muscle.

Fabrizio Pin, Marc Beltrà, Lorena Garcia-Castillo, Barbara Pardini, Giovanni Birolo, Giuseppe Matullo, Fabio Penna, Denis Guttridge, Paola Costelli.

  BACKGROUND: Cachexia, a syndrome frequently occurring in cancer patients, is characterized by muscle wasting, altered energy and protein metabolism and impaired myogenesis. Tumour-derived microvesicles (TMVs) containing proteins, messenger RNAs (mRNAs), and non-coding RNAs could contribute to cancer-induced muscle wasting.METHODS: Differential ultracentrifugation was used to isolate TMVs from the conditioned medium of Lewis lung carcinoma and C26 colon carcinoma cell cultures. TMVs were added to the culture medium of C2C12 myoblasts and myotubes for 24-48-72 h, and the effects on protein and energy metabolism were assessed. TMVs were also isolated from the blood of C26-bearing mice. MicroRNA (miR) profile of TMVs was obtained by RNA-seq and validated by digital drop PCR. Selected miRs were overexpressed in C2C12 myoblasts to assess the effects on myogenic differentiation.
RESULTS: Differentiation was delayed in C2C12 myoblasts exposed to TMVs, according to reduced expression of myosin heavy chain (MyHC; about 62% of controls at Day 4) and myogenin (about 68% of controls at Day 4). As for myotubes, TMVs did not affect the expression of MyHC, while revealed able to modulate mitochondria and oxidative metabolism. Indeed, reduced mRNA levels of PGC-1α (C = 1 ± 0.2, TMV = 0.57 ± 0.06, normalized fold change, P < 0.05) and Cytochrome C (C = 1 ± 0.2, TMV = 0.65 ± 0.04, normalized fold change, P < 0.05), associated with increased BNIP3 expression (C = 1 ± 0.1, TMV = 1.29 ± 0.2, normalized fold change, P < 0.05), were observed, suggesting reduced mitochondrial biogenesis/amount and enhanced mitophagy. These changes were paralleled by decreased oxygen consumption (C = 686.9 ± 44 pmol/min, TMV = 552.25 ± 24 pmol/min, P < 0.01) and increased lactate levels (C = 0.0063 ± 0.00045 nmol/μL, TMV = 0.0094 ± 0.00087 nmol/μL, P < 0.01). A total of 118 miRs were found in MVs derived from the plasma of the C26 hosts; however, only three of them were down-regulated (RNA-seq): miR-181a-5p (-1.46 fold change), miR-375-3p (-2.52 fold change), and miR-455-5p (-3.87 fold change). No correlation could be observed among miRs in the MVs obtained from the blood of the C26 host and those released by C26 cells in the culture medium. Overexpression of miR-148a-3p and miR-181a-5p in C2C12 myoblasts revealed the ability to impinge on the mRNA levels of Myf5, Myog, and MyHC (Myh4 and Myh7).
CONCLUSIONS: These results show that in C2C12 cultures, TMVs are able to affect both differentiation and the mitochondrial system. Such effects could be related to TMV-contained miRs.

Keywords:  Cancer cachexia; MicroRNAs; Microvesicles; Mitochondria; Muscle wasting; Myogenesis

DOI:  https://doi.org/10.1002/jcsm.12844
Life (Basel). 2021 Nov 27. pii: 1304. [Epub ahead of print]11(12):

The Implication of Autophagy in Gastric Cancer Progression.

Evangelos Koustas, Eleni-Myrto Trifylli, Panagiotis Sarantis, Nikolaos I Kontolatis, Christos Damaskos, Nikolaos Garmpis, Christos Vallilas, Anna Garmpi, Athanasios G Papavassiliou, Michalis V Karamouzis.

  Gastric cancer is the fifth most common malignancy and the third leading cause of cancer-related death worldwide. The three entirely variable entities have distinct epidemiology, molecular characteristics, prognosis, and strategies for clinical management. However, many gastric tumors appear to be resistant to current chemotherapeutic agents. Moreover, a significant number of gastric cancer patients, with a lack of optimal treatment strategies, have reduced survival. In recent years, multiple research data have highlighted the importance of autophagy, an essential catabolic process of cytoplasmic component digestion, in cancer. The role of autophagy as a tumor suppressor or tumor promoter mechanism remains controversial. The multistep nature of the autophagy process offers a wide array of targetable points for designing novel chemotherapeutic strategies. The purpose of this review is to summarize the current knowledge regarding the interplay between gastric cancer development and the autophagy process and decipher the role of autophagy in this kind of cancer. A plethora of different agents that direct or indirect target autophagy may be a novel therapeutic approach for gastric cancer patients.

Keywords:  autophagy; autophagy inducers; autophagy inhibitors; autophagy regulation; chemotherapy; gastric cancer

DOI:  https://doi.org/10.3390/life11121304
Life (Basel). 2021 Dec 20. pii: 1439. [Epub ahead of print]11(12):

MicroRNAs as Potential Biomarkers for Exercise-Based Cancer Rehabilitation in Cancer Survivors.

Yanping Jiang, Kulsoom Ghias, Sanjeev Gupta, Ananya Gupta.

  Expression and functions of microRNAs (miRNAs) have been widely investigated in cancer treatment-induced complications and as a response to physical activity, respectively, but few studies focus on the application of miRNAs as biomarkers in exercise-based cancer rehabilitation. Research has shown that certain miRNA expression is altered substantially due to tissue damage caused by cancer treatment and chronic inflammation. MiRNAs are released from the damaged tissue and can be easily detected in blood plasma. Levels of the miRNA present in peripheral circulation can therefore be used to measure the extent of tissue damage. Moreover, damage to tissues such as cardiac and skeletal muscle significantly affects the individual's health-related fitness, which can be determined using physiologic functional assessments. These physiologic parameters are a measure of tissue health and function and can therefore be correlated with the levels of circulating miRNAs. In this paper, we reviewed miRNAs whose expression is altered during cancer treatment and may correlate to physiological, physical, and psychological changes that significantly impact the quality of life of cancer survivors and their role in response to physical activity. We aim to identify potential miRNAs that can not only be used for monitoring changes that occur in health-related fitness during cancer treatment but can also be used to evaluate response to exercise-based rehabilitation and monitor individual progress through the rehabilitation programme.

Keywords:  cancer survivorship care; miRNA; molecular biomarker; personalized exercise intervention; rehabilitation

DOI:  https://doi.org/10.3390/life11121439
Antioxidants (Basel). 2021 Nov 29. pii: 1912. [Epub ahead of print]10(12):

Oxidative Stress in ICU Patients: ROS as Mortality Long-Term Predictor.

Juan Carlos Ayala, Adriana Grismaldo, Luis Gonzalo Sequeda-Castañeda, Andrés Felipe Aristizábal-Pachón, Ludis Morales.

  Lipid peroxidation, protein oxidation, and mutations in mitochondrial DNA generate reactive oxygen species (ROS) that are involved in cell death and inflammatory response syndrome. ROS can also act as a signal in the intracellular pathways involved in normal cell growth and homeostasis, as well as in response to metabolic adaptations, autophagy, immunity, differentiation and cell aging, the latter of which is an important characteristic in acute and chronic pathologies. Thus, the measurement of ROS levels of critically ill patients, upon admission, enables a prediction not only of the severity of the inflammatory response, but also of its subsequent potential outcome. The aim of this study was to measure the levels of mitochondrial ROS (superoxide anion) in the peripheral blood lymphocytes within 24 h of admission and correlate them with survival at one year after ICU and hospital discharge. We designed an observational prospective study in 51 critical care patients, in which clinical variables and ROS production were identified and correlated with mortality at 12 months post-ICU hospitalization. Oxidative stress levels, measured as DHE fluorescence, show a positive correlation with increased long-term mortality. In ICU patients the major determinant of survival is oxidative stress, which determines inflammation and outlines the cellular response to inflammatory stimuli.

Keywords:  critically ill; reactive oxygen species; sepsis; survival

DOI:  https://doi.org/10.3390/antiox10121912
Front Cell Dev Biol. 2021 ;9 784424

Weight Loss in Cancer Patients Correlates With p38β MAPK Activation in Skeletal Muscle.

Guohua Zhang, Lindsey J Anderson, Song Gao, Thomas K Sin, Zicheng Zhang, Hongyu Wu, Syed H Jafri, Solomon A Graf, Peter C Wu, Atreya Dash, Jose M Garcia, Yi-Ping Li.

  Unintentional weight loss, a first clinical sign of muscle wasting, is a major threat to cancer survival without a defined etiology. We previously identified in mice that p38β MAPK mediates cancer-induced muscle wasting by stimulating protein catabolism. However, whether this mechanism is relevant to humans is unknown. In this study, we recruited men with cancer and weight loss (CWL) or weight stable (CWS), and non-cancer controls (NCC), who were consented to rectus abdominis (RA) biopsy and blood sampling (n = 20/group). In the RA of both CWS and CWL, levels of activated p38β MAPK and its effectors in the catabolic pathways were higher than in NCC, with progressively higher active p38β MAPK detected in CWL. Remarkably, levels of active p38β MAPK correlated with weight loss. Plasma analysis for factors that activate p38β MAPK revealed higher levels in some cytokines as well as Hsp70 and Hsp90 in CWS and/or CWL. Thus, p38β MAPK appears a biomarker of weight loss in cancer patients.

Keywords:  C/EBPbeta; Hsp70; Hsp90; P300; UBR2; ULK1

DOI:  https://doi.org/10.3389/fcell.2021.784424
Antioxidants (Basel). 2021 Nov 25. pii: 1883. [Epub ahead of print]10(12):

Pardaxin Activates Excessive Mitophagy and Mitochondria-Mediated Apoptosis in Human Ovarian Cancer by Inducing Reactive Oxygen Species.

Yen-Po Chen, Po-Chang Shih, Chien-Wei Feng, Chang-Cheng Wu, Kuan-Hao Tsui, You-Hsien Lin, Hsiao-Mei Kuo, Zhi-Hong Wen.

  Most ovarian cancer (OC) patients are diagnosed with stage III or higher disease, resulting in a poor prognosis. Currently, paclitaxel combined with carboplatin shows the best treatment outcome for OC. However, no effective drug is available for patients that do not respond to treatment; thus, new drugs for OC are needed. We evaluated the antimicrobial peptide, pardaxin, in PA-1 and SKOV3 cells. Pardaxin induced apoptosis as determined by MTT and TUNEL assays, as well as activation of caspases-9/3, Bid, t-Bid, and Bax, whereas Bcl-2 was downregulated. The IC50 values for pardaxin were 4.6-3.0 μM at 24 and 48 h. Mitochondrial and intracellular reactive oxygen species (ROS) were overproduced and associated with disrupted mitochondrial membrane potential and respiratory capacity. Additionally, the mitochondrial network was fragmented with downregulated fusogenic proteins, MFN1/2 and L-/S-OPA1, and upregulated fission-related proteins, DRP1 and FIS1. Autophagy was also activated as evidenced by increased expression of autophagosome formation-related proteins, Beclin, p62, and LC3. Enhanced mitochondrial fragmentation and autophagy indicate that mitophagy was activated. ROS-induced cytotoxicity was reversed by the addition of N-acetylcysteine, confirming ROS overproduction as a contributor. Taken together, pardaxin demonstrated promising anticancer activity in OC cells, which warrants further preclinical development of this compound.

Keywords:  apoptosis; autophagosome; mitochondria; mitochondrial membrane potential; mitophagy; natural product; ovarian cancer; oxidative phosphorylation; pardaxin; reactive oxygen species

DOI:  https://doi.org/10.3390/antiox10121883
Cell Biol Int. 2021 Dec 22.

Overexpression of NDUFV1 alleviates renal damage by improving mitochondrial function in unilateral ureteral obstruction model mice.

Ruiting Wang, Chen Kairen, Lu Li, Lingling Zhang, Haifeng Gong, Xinzhong Huang.

  Mitochondrial homeostasis plays essential roles for the proper functioning of the kidney. NADH-Ubiquinone Oxidoreductase Core Subunit V1 (NDUFV1) is an enzyme in the complex I of electron transfer chain (ETC) in mitochondria. In the present study, we examined the effects of NDUFV1 on renal function in unilateral ureteral obstruction (UUO) model mice. Our data showed that increased expression of NDUFV1 improves kidney function as evidenced by the decreases in blood urea nitrogen and serum creatinine in UUO mice. Moreover, NDUFV1 also maintains renal structures and alleviates renal fibrosis induced by UUO surgery. Mechanistically, NDUFV1 mitigates the increased oxidative stress in the kidney in UUO model mice. Meanwhile, increased expression of NDUFV1 in the kidney improves the integrity of the complex I and potentiates the complex I activity. Overall, these results indicate that the ETC complex I plays beneficial roles against renal dysfunction induced by acute kidney injury such as UUO. Therefore, NDUFV1 might be a druggable target for developing agents for dealing with disabled mitochondria associated renal diseases. This article is protected by copyright. All rights reserved.

Keywords:  NDUFV1; mitochondria; nephropathy; oxidative stress; unilateral ureteral obstruction

DOI:  https://doi.org/10.1002/cbin.11736
Acta Biochim Pol. 2021 Dec 22.

Muscle adaptation to sleeve gastrectomy: Potential role of nutritional supplementation and physical exercise.

Entesar Ali Saber, Neven Makram Aziz, Mohammed Mustafa Abd El Aleem, Maha Yehia Kamel, Seham A Abd El-Aleem, Fatma Farrag Ali, Doaa Mohamed Elroby Ali, Amira Fathi Behery.

Skeletal muscle is metabolically and functionally flexible and contractile under normal conditions. Obesity is a risk factor that causes metabolic disorders and reduces muscle contractility. Sleeve gastrectomy (SG) has been used for surgical correction of obesity. This work aimed to investigate how obesity and its surgical correction affects skeletal muscle and the possible role of nutritional supplementation and physical exercise. Adult male albino rats were randomly divided into five groups, 8 rats per group: group Ia (control non-obese), group Ib (control obese), group II (post-operative, SG), group III (post SG + nutritional supplementation) and group IV (post SG + nutritional supplementation + physical exercise). SG resulted in cellular and metabolic degenerative disorders in the muscle including wasting, weakness and fibrosis with elevated inflammatory, oxidative and injury markers. Nutritional supplementation induced the post SG muscle regeneration indicated by high expression of insulin growth factor-1 (IGF-1) and myogenin and low expression of transforming growth factor beta 1 (TGF-β1). Interestingly, it improved the metabolic state of the muscle by reducing the oxidative stress, inflammatory and muscle injury markers and delaying the onset of fatigue. What is more, physical exercise along with nutritional supplementation resulted in further improvement of the muscle metabolic state and function. In conclusion, nutritional supplementations together with physical exercise after SG are essential for preserving muscle mass and contractility and improving its metabolic and functional status.

DOI: https://doi.org/10.18388/abp.2020_5565
Cells. 2021 Dec 01. pii: 3382. [Epub ahead of print]10(12):

Differential Effects of 25-Hydroxyvitamin D3 versus 1α 25-Dihydroxyvitamin D3 on Adipose Tissue Browning in CKD-Associated Cachexia.

Robert H Mak, Uwe Querfeld, Alex Gonzalez, Sujana Gunta, Wai W Cheung.

  Patients with chronic kidney disease (CKD) often have low serum concentrations of 25(OH)D3 and 1,25(OH)2D3. We investigated the differential effects of 25(OH)D3 versus 1,25(OH)2D3 repletion in mice with surgically induced CKD. Intraperitoneal supplementation of 25(OH)D3 (75 μg/kg/day) or 1,25(OH)2D3 (60 ng/kg/day) for 6 weeks normalized serum 25(OH)D3 or 1,25(OH)2D3 concentrations in CKD mice, respectively. Repletion of 25(OH)D3 normalized appetite, significantly improved weight gain, increased fat and lean mass content and in vivo muscle function, as well as attenuated elevated resting metabolic rate relative to repletion of 1,25(OH)2D3 in CKD mice. Repletion of 25(OH)D3 in CKD mice attenuated adipose tissue browning as well as ameliorated perturbations of energy homeostasis in adipose tissue and skeletal muscle, whereas repletion of 1,25(OH)2D3 did not. Significant improvement of muscle fiber size and normalization of fat infiltration of gastrocnemius was apparent with repletion of 25(OH)D3 but not with 1,25(OH)2D3 in CKD mice. This was accompanied by attenuation of the aberrant gene expression of muscle mass regulatory signaling, molecular pathways related to muscle fibrosis as well as muscle expression profile associated with skeletal muscle wasting in CKD mice. Our findings provide evidence that repletion of 25(OH)D3 exerts metabolic advantages over repletion of 1,25(OH)2D3 by attenuating adipose tissue browning and muscle wasting in CKD mice.

Keywords:  1α; 25-dihydroxyvitamin D3; 25-hydroxyvitamin D3; adipose tissue browning; cachexia; chronic kidney disease; muscle wasting; vitamin D insufficiency

DOI:  https://doi.org/10.3390/cells10123382
Cells. 2021 Dec 14. pii: 3527. [Epub ahead of print]10(12):

Decreased miR-497-5p Suppresses IL-6 Induced Atrophy in Muscle Cells.

Paula P Freire, Sarah S Cury, Letícia O Lopes, Geysson J Fernandez, Jianming Liu, Leonardo Nazario de Moraes, Grasieli de Oliveira, Jakeline S Oliveira, Diogo de Moraes, Otavio Cabral-Marques, Maeli Dal-Pai-Silva, Xiaoyun Hu, Da-Zhi Wang, Robson F Carvalho.

  Interleukin-6 (IL-6) is a pro-inflammatory cytokine associated with skeletal muscle wasting in cancer cachexia. The control of gene expression by microRNAs (miRNAs) in muscle wasting involves the regulation of thousands of target transcripts. However, the miRNA-target networks associated with IL6-induced muscle atrophy remain to be characterized. Here, we show that IL-6 promotes the atrophy of C2C12 myotubes and changes the expression of 20 miRNAs (5 up-regulated and 15 down-regulated). Gene Ontology analysis of predicted miRNAs targets revealed post-transcriptional regulation of genes involved in cell differentiation, apoptosis, migration, and catabolic processes. Next, we performed a meta-analysis of miRNA-published data that identified miR-497-5p, a down-regulated miRNAs induced by IL-6, also down-regulated in other muscle-wasting conditions. We used miR-497-5p mimics and inhibitors to explore the function of miR-497-5p in C2C12 myoblasts and myotubes. We found that miR-497-5p can regulate the expression of the cell cycle genes CcnD2 and CcnE1 without affecting the rate of myoblast cellular proliferation. Notably, miR-497-5p mimics induced myotube atrophy and reduced Insr expression. Treatment with miR-497-5p inhibitors did not change the diameter of the myotubes but increased the expression of its target genes Insr and Igf1r. These genes are known to regulate skeletal muscle regeneration and hypertrophy via insulin-like growth factor pathway and were up-regulated in cachectic muscle samples. Our miRNA-regulated network analysis revealed a potential role for miR-497-5p during IL6-induced muscle cell atrophy and suggests that miR-497-5p is likely involved in a compensatory mechanism of muscle atrophy in response to IL-6.

Keywords:  Interleukin-6; inflammation; microRNAs; muscle wasting

DOI:  https://doi.org/10.3390/cells10123527
J Cachexia Sarcopenia Muscle. 2021 Dec 23.

The contributory role of vascular health in age-related anabolic resistance.

Nile F Banks, Emily M Rogers, David D Church, Arny A Ferrando, Nathaniel D M Jenkins.

  Sarcopenia, or the age-related loss of skeletal muscle mass and function, is an increasingly prevalent condition that contributes to reduced quality of life, morbidity, and mortality in older adults. Older adults display blunted anabolic responses to otherwise anabolic stimuli-a phenomenon that has been termed anabolic resistance (AR)-which is likely a casual factor in sarcopenia development. AR is multifaceted, but historically much of the mechanistic focus has been on signalling impairments, and less focus has been placed on the role of the vasculature in postprandial protein kinetics. The vascular endothelium plays an indispensable role in regulating vascular tone and blood flow, and age-related impairments in vascular health may impede nutrient-stimulated vasodilation and subsequently the ability to deliver nutrients (e.g. amino acids) to skeletal muscle. Although the majority of data has been obtained studying younger adults, the relatively limited data on the effect of blood flow on protein kinetics in older adults suggest that vasodilatory function, especially of the microvasculature, strongly influences the muscle protein synthetic response to amino acid feedings. In this narrative review, we examine evidence of AR in older adults following amino acid and mixed meal consumption, examine the evidence linking vascular dysfunction and insulin resistance to age-related AR, review the influence of nitric oxide and endothelin-1 on age-related vascular dysfunction as it relates to AR, briefly review the potential causal role of arterial stiffness in promoting skeletal muscle microvascular dysfunction and AR, and provide a brief overview and future considerations for research examining age-related AR.

Keywords:  Ageing; Anabolic resistance; Blood flow; Insulin; Muscle protein synthesis; Vasodilation

DOI:  https://doi.org/10.1002/jcsm.12898
Cancer Med. 2021 Dec 24.

Neurobiology of cancer: Definition, historical overview, and clinical implications.

Boris Mravec.

  Studies published in the last two decades have clearly demonstrated that the nervous system plays a significant role in carcinogenesis, the progression of cancer, and the development of metastases. These studies, combining oncological and neuroscientific approaches, created the basis for the emergence of a new field in oncology research, the so-called "neurobiology of cancer." The concept of the neurobiology of cancer is based on several facts: (a) psychosocial factors influence the incidence and progression of cancer diseases; (b) the nervous system affects DNA mutations and oncogene-related signaling; (c) the nervous system modulates tumor-related immune responses; (d) tumor tissues are innervated; (e) neurotransmitters released from nerves innervating tumor tissues affect tumor growth and metastasis; (f) alterations or modulation of nervous system activity affects the incidence and progression of cancers; (g) tumor tissue affects the nervous system. The aim of this review is to characterize the pillars that create the basis of cancer neurobiology, to describe recent research advances of the nervous system's role in cancer diseases, and to depict potential clinical implications for oncology.

Keywords:  adrenergic signaling; epinephrine; hypothalamic-pituitary-adrenocortical axis; innervation; neurobiology of cancer; norepinephrine; propranolol; psychoneuroimmunology; stress; sympathoadrenal system; β-blockers

DOI:  https://doi.org/10.1002/cam4.4488
Int J Mol Sci. 2021 Dec 14. pii: 13435. [Epub ahead of print]22(24):

Targeting Mitochondrial OXPHOS and Their Regulatory Signals in Prostate Cancers.

Chia-Lin Chen, Ching-Yu Lin, Hsing-Jien Kung.

  Increasing evidence suggests that tumor development requires not only oncogene/tumor suppressor mutations to drive the growth, survival, and metastasis but also metabolic adaptations to meet the increasing energy demand for rapid cellular expansion and to cope with the often nutritional and oxygen-deprived microenvironment. One well-recognized strategy is to shift the metabolic flow from oxidative phosphorylation (OXPHOS) or respiration in mitochondria to glycolysis or fermentation in cytosol, known as Warburg effects. However, not all cancer cells follow this paradigm. In the development of prostate cancer, OXPHOS actually increases as compared to normal prostate tissue. This is because normal prostate epithelial cells divert citrate in mitochondria for the TCA cycle to the cytosol for secretion into seminal fluid. The sustained level of OXPHOS in primary tumors persists in progression to an advanced stage. As such, targeting OXPHOS and mitochondrial activities in general present therapeutic opportunities. In this review, we summarize the recent findings of the key regulators of the OXPHOS pathway in prostate cancer, ranging from transcriptional regulation, metabolic regulation to genetic regulation. Moreover, we provided a comprehensive update of the current status of OXPHOS inhibitors for prostate cancer therapy. A challenge of developing OXPHOS inhibitors is to selectively target cancer mitochondria and spare normal counterparts, which is also discussed.

Keywords:  OXPHOS; cancer therapy; mitochondria

DOI:  https://doi.org/10.3390/ijms222413435
Am J Physiol Gastrointest Liver Physiol. 2021 Dec 22.

LPS induces rapid increase in GDF15 levels in mice, rats and humans but is not required for anorexia in mice.

Anita Patel, Henriette Frikke-Schmidt, Olivier Bezy, Paul V Sabatini, Nikolaj Rittig, Niels Jessen, Martin G Myers, Randy J Seeley.

  Growth differentiation factor 15 (GDF15), a TGFβ superfamily cytokine, acts through its receptor, GDNF-family receptor α-like (GFRAL), to suppress food intake and promote nausea. GDF15 is broadly expressed at low levels but increases in states of disease such as cancer, cachexia, and sepsis. Whether GDF15 is necessary for inducing sepsis associated anorexia and body weight loss is currently unclear. To test this we used a model of moderate systemic infection in GDF15KO and GFRALKO mice with lipopolysaccharide (LPS) treatment to define the role of GDF15 signaling in infection-mediated physiologic responses. Since physiologic responses to LPS depend on housing temperature, we tested the effects of subthermoneutral and thermoneutral conditions on eliciting anorexia and inducing GDF15. Our data demonstrate a conserved LPS-mediated increase in circulating GDF15 levels in mouse, rat and human. However, we did not detect differences in LPS induced anorexia between WT and GDF15KO or GFRALKO mice. Further, there were no differences in anorexia or circulating GDF15 levels at either thermoneutral or subthermoneutral housing conditions in LPS treated mice. These data demonstrate that GDF15 is not necessary to drive food intake suppression in response to moderate doses of LPS.

Keywords:  GDF-15; GFRAL; LPS; anorexia; thermoneutrality

DOI:  https://doi.org/10.1152/ajpgi.00146.2021