bims-aucach 2022-03-20 papers

bims-aucach

Biomed News

on Autophagy and cachexia

Issue of 2022–03–20
eleven papers selected by
Kleiton Silva, Rowan University

Muscle Wasting in COPD: Not Enough Autophagy?
Exercise in People With Cancer: A Spotlight on Energy Regulation and Cachexia.
Comparison of frailty, sarcopenia and protein energy wasting in a contemporary peritoneal dialysis cohort.
Muscle wasting assessment tools for prostate cancer.
Mapping ongoing nutrition intervention trials in muscle, sarcopenia, and cachexia: a scoping review of future research.
The regulation of autophagy by the miR-199a-5p/p62 axis was a potential mechanism of small cell lung cancer cisplatin resistance.
Moderate aerobic exercise on bone quality changes associated with aging and oxidative stress in BALB/c mice.
The beneficial effects of intradialytic parenteral nutrition in hemodialysis patients with protein energy wasting: a prospective randomized controlled trial.
Effect of running exercise on titanium dioxide (TiO2)-induced chronic arthritis and sarcopenia in mice. A titanium prosthesis loosening injury model study.
A Novel Application of Serum Creatinine and Cystatin C to Predict Sarcopenia in Advanced CKD.
Defective mitophagy and induction of apoptosis by the depleted levels of PINK1 and parkin in Pb and β-amyloid peptide induced toxicity.

Am J Respir Cell Mol Biol. 2022 Mar 16.

Muscle Wasting in COPD: Not Enough Autophagy?

Jean-Philippe Leduc-Gaudet, Sabah N A Hussain.



Keywords:  Autophagy; COPD; Myogenesis; Satellite Cells; Skeletal muscle

DOI:  https://doi.org/10.1165/rcmb.2022-0064ED
Front Physiol. 2022 ;13 836804

Exercise in People With Cancer: A Spotlight on Energy Regulation and Cachexia.

Jessica Allan, Linda A Buss, Nick Draper, Margaret J Currie.

  Exercise is increasingly becoming a standard of cancer care, with well-documented benefits for patients including improved mental wellbeing and reduced treatment-related side effects. However, important gaps in knowledge remain about how to optimise exercise prescription for people with cancer. Importantly, it remains unclear how exercise affects the progression of cancer cachexia (a wasting disease stemming from energy imbalance, and a common manifestation of advanced malignant disease), particularly once the condition has already developed. It was recently suggested that the anti-tumour effect of exercise might come from improved energetic capacity. Here, we highlight the possible effect of exercise on energetic capacity and energy regulation in the context of cancer, and how this might affect the progression of cancer cachexia. We suggest that due to the additional energy demand caused by the tumour and associated systemic inflammation, overreaching may occur more easily in people with cancer. Importantly, this could result in impaired anti-tumour immunity and/or the exacerbation of cancer cachexia. This highlights the importance of individualised exercise programs for people with cancer, with special consideration for the regulation of energy balance, ongoing monitoring and possible nutritional supplementation to support the increased energy demand caused by exercise.

Keywords:  cancer cachexia; energetic capacity; energy regulation; exercise oncology; inflammation

DOI:  https://doi.org/10.3389/fphys.2022.836804
Perit Dial Int. 2022 Mar 15. 8968608221077462

Comparison of frailty, sarcopenia and protein energy wasting in a contemporary peritoneal dialysis cohort.

Andrew Davenport.

   BACKGROUND: More elderly frail patients are now treated by peritoneal dialysis (PD). Frailty, sarcopenia and protein energy wasting (PEW) are all associated with increased mortality. Simple screening tools are required to identify patients to allow for interventions. As such, we wished to review the prevalence of frailty and compare frailty with sarcopenia and PEW in a contemporary PD population.
PATIENTS AND METHODS: We used the Clinical Frailty Score (CFS) to determine frailty, bio-impedance body composition and hand grip strength (HGS) to determine sarcopenia and combining laboratory, body composition and protein nitrogen appearance rate (PNA) to assess PEW.
RESULTS: Records of 368 PD patients, 61% male, mean age 60.9 ± 16.1 years, body mass index (BMI) 26.2 ± 5.1 kg/m2 were reviewed, with 71 classified as frail (19.3%; CFS > 4), and frailty associated with age (odds ratio (OR) 1.047, 95% confidence interval (CL) 1.01-1.085, p = 0.012), Stoke-Davies co-morbidity (OR 1.808, 95%CL 1.129-2.895, p = 0.014) and negatively with HGS (OR 0.906, 95% CL 0.897-0.992, p = 0.033); 17.7% met muscle loss and HGS criteria for sarcopenia, with fair agreement with frailty (kappa 0.24 (CL 0.09-0.38)). Only two patients (0.5%) met all four criteria for PEW, 26.1% met the reduced BMI criteria, 4.6% the serum albumin, 32.9% the PNA and 39.4% the reduced muscle mass. HGS correlated with lean muscle mass (r 2 = 0.42, p < 0.001).
CONCLUSION: Using the CFS, 19.3% of patients were classified as frail, compared to 17.7% with sarcopenia and <1% with PEW. The CFS requires no special equipment or laboratory tests and was associated with age, co-morbidity and HGS weakness.

Keywords:  Bio-impedance; co-morbidity; frailty; hand grip strength; peritoneal dialysis; protein energy wasting; sarcopenia

DOI:  https://doi.org/10.1177/08968608221077462
Sci Rep. 2022 Mar 18. 12(1): 4662

Muscle wasting assessment tools for prostate cancer.

Alan Espinosa-Marrón, Aquiles Rubio-Blancas, Christian Aníbal Quiñones-Capistran, Anais Camacho-Zamora, Itzel Salcedo-Grajales, Ana Paula Bravo-García, Maria T Bourlon, Ricardo A Castillejos-Molina, Julie-Alexia Dias, María Del Pilar Milke-García.

Prostate cancer and its treatment may induce muscle wasting. Body composition and muscle functionality are rarely assessed in patients with prostate cancer from developing countries due to the limited availability of high-quality equipment for routine diagnosis. This cross-sectional study evaluated the association between several simplistic techniques for assessing muscle mass and function with a more complex standard of reference for muscle wasting among Mexican men with prostate cancer. Muscle wasting was highly prevalent, yet it was presumably associated with aging rather than cancer and its treatment itself. The restricted availability of specific equipment in clinical settings with technological limitations supports using unsophisticated techniques as surrogate measurements for muscle wasting. The left-arm handgrip dynamometry displayed the highest correlation with the standard of reference and exhibited an acceptable predicted probability for muscle estimation. Combining several simplistic techniques may be preferable. We also developed and internally validated a manageable model that helps to identify elderly patients with prostate cancer at risk of muscle depletion and impairment. These findings promote the early recognition and treatment of muscle wasting alterations occurring among older adults with prostate cancer.

DOI: https://doi.org/10.1038/s41598-022-08501-9
J Cachexia Sarcopenia Muscle. 2022 Mar 17.

Mapping ongoing nutrition intervention trials in muscle, sarcopenia, and cachexia: a scoping review of future research.

Camila E Orsso, Montserrat Montes-Ibarra, Merran Findlay, Barbara S van der Meij, Marian A E de van der Schueren, Francesco Landi, Alessandro Laviano, Carla M Prado.

  Muscle loss alone, or in the context of sarcopenia or cachexia, is a prevalent condition and a predictor of negative outcomes in aging and disease. As adequate nutrition is essential for muscle maintenance, a growing number of studies has been conducted to explore the role of specific nutrients on muscle mass or function. Nonetheless, more research is needed to guide evidence-based recommendations. This scoping review aimed to compile and document ongoing clinical trials investigating nutrition interventions as a strategy to prevent or treat low muscle mass or function (strength and physical performance), sarcopenia, or cachexia. ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform were searched up to 21 April 2021 for planned and ongoing trials. Randomized controlled trials with ≥20 participants per arm were included based on intent to explore the effects of nutrition interventions on muscle-related outcomes (i.e. muscle mass or strength, physical performance, or muscle synthesis rate) in both clinical and non-clinical conditions (i.e. aging). Two reviewers independently screened records for eligibility, and a descriptive synthesis of trials characteristics was conducted. A total of 113 trials were included in the review. Most trials (69.0%) enroll adults with clinical conditions, such as cancer (19.5%), obesity and metabolic diseases (16.8%), and musculoskeletal diseases (10.7%). The effects of nutrition interventions on age-related muscle loss are explored in 31% of trials. Although nutrition interventions of varied types were identified, food supplements alone (48.7%) or combined with dietary advice (11.5%) are most frequently reported. Protein (17.7%), amino acids (10.6%), and β-hydroxy-β-methylbutyrate (HMB, 6.2%) are the top three food supplements' nutrients under investigation. Primary outcome of most trials (54.9%) consists of measures of muscle mass alone or in combination with muscle strength and/or performance (as either primary or secondary outcomes). Muscle strength and physical performance are primary outcomes of 38% and 31.9% of the trials, respectively. These measurements were obtained using a variety of techniques. Only a few trials evaluate muscle synthesis rate either as a primary or secondary outcome (5.3%). Several nutrition studies focusing on muscle, sarcopenia, and cachexia are underway and can inform future research in this area. Although many trials have similar type of interventions, methodological heterogeneity may challenge study comparisons, and future meta-analyses aiming to provide evidence-based recommendations. Upcoming research in this area may benefit from guidelines for the assessment of therapeutic effects of nutrition interventions.

Keywords:  Cachexia; Clinical trials; Dietary intervention; Muscle; Nutrition intervention; Sarcopenia

DOI:  https://doi.org/10.1002/jcsm.12954
Cancer Cell Int. 2022 Mar 15. 22(1): 120

The regulation of autophagy by the miR-199a-5p/p62 axis was a potential mechanism of small cell lung cancer cisplatin resistance.

Tiezhi Li, Helin Zhang, Zhichao Wang, Shaolin Gao, Xu Zhang, Haiyong Zhu, Na Wang, Honglin Li.

   BACKGROUND: Autophagy has been found to be involved in the multidrug resistance (MDR) of cancers, but whether it is associated with resistance of small cell lung cancer (SCLC) has not been studied. Here, we hypothesized that a potential autophagy-regulating miRNA, miR-199a-5p, regulated cisplatin-resistant SCLC.
METHODS: We validated the MDR of H446/EP using CCK-8 and LDH. We tested the binding of miR-199a-5p to p62 using the Dual-Luciferase assay and validated the association of miR-199a-5p and p62 in SCLC samples. We overexpressed (OE) and knocked down (KD) miR-199a-5p in H446 and H446/EP and determined the expression of miR-199a-5p, autophagy-related proteins, and the formation of autophagolysosomes using QPCR, western blotting, and MDC staining respectively. These results were validated in an orthotopic H446 mouse model of SCLC.
RESULTS: H446/EP was resistant to cisplatin, etoposide, paclitexal, epirubicin, irinotecan, and vinorelbine. Exposure of cisplatin at 5 μg/ml for 24 h increased LC3II/LC3I, ATG5, p62, and the formation of autophagolysosomes in H446 cells, but not in H446/EP cells. The expression of miR-199a-5p was up-regulated in H446/EP compared to H446. MiR-199a-5p directly targeted the p62 gene. The expression of miR-199a-5p and p62 were correlated in SCLC samples. In H446 and H69PR, the OE of miR-199a-5p increased LC3II/LC3I, p62, and the formation of autophagolysosomes, but not ATG5, while the KD of miR-199a-5p decreased p62, but did not affect LC3II/LC3I, ATG5, and the formation of autophagolysosomes. In H446/EP, the OE of miR-199a-5p decreased p62 only. These results were generally consistent to results in the animal tumor samples.
CONCLUSIONS: The regulation of autophagy by the miR-199a-5p/p62 axis was a potential mechanism of small cell lung cancer cisplatin resistance.

Keywords:  Autophagy; Cisplatin; H446; MDR; MiR-199a-5p; p62

DOI:  https://doi.org/10.1186/s12935-022-02505-1
J Biomech. 2022 Mar 10. pii: S0021-9290(22)00091-4. [Epub ahead of print]135 111035

Moderate aerobic exercise on bone quality changes associated with aging and oxidative stress in BALB/c mice.

José Alfredo Sierra-Ramírez, Lourdes Saucedo-Bueno, Ana Lilia García-Hernández, Arnulfo Martínez-Dávalos, Camilo Rodríguez-López, Maria Elisa Drago-Serrano, Marycarmen Godínez-Victoria.

  Exercise encourages active and healthy aging, maintaining functional and physical capabilities. This study aimed to assess the effects of a long-term moderate aerobic exercise protocol on bone microarchitecture and fragility associated with chronic inflammation and oxidative stress in aging. Male BALB/c mice (n = 10 per group) underwent a moderate exercise protocol from 13 weeks to 27 (adulthood age) or 108 weeks of age (elderly age) and were then sacrificed. Age-match sedentary mice were included as a control group. Serum cortisol concentrations were determined by chemiluminescent immunoassay, C-reactive protein (CRP) by a turbidimetric assay, advanced glycation end-products (AGEs) and malondialdehyde (MDA) by fluorescent spectroscopy, and total glutathione (GSH) by colorimetric method. The right femur was dissected formorphometric and densitometricanalysis bycomputerized microtomography (µCT),and biomechanical properties were assessed usinga three-point bending device. Musclefrom the same extremitywas obtained to determine relative mRNA expression ofpro-inflammatory cytokines (TNF-α and IL-6) by RT-qPCR.Statistical differences were evaluated by two-way ANOVA and Holm-Sidak method post hoc with P < 0.05. In elderly mice, moderate exercise increased glutathione levels and microarchitecture complexity but decreased bone fragility and oxidative stress markers, cortisol, and pro-inflammatory cytokines. In conclusion, these results suggest a strong link between a pro-inflammatory state and age-conditioned oxidative stress on bone quality. Thus, on a human scale, moderate aerobic exercise may improve bone quality during aging.

Keywords:  Aging; Inflammation; Moderate exercise; Oxide-reduction system; Quality bone

DOI:  https://doi.org/10.1016/j.jbiomech.2022.111035
Sci Rep. 2022 Mar 16. 12(1): 4529

The beneficial effects of intradialytic parenteral nutrition in hemodialysis patients with protein energy wasting: a prospective randomized controlled trial.

Piyawan Kittiskulnam, Athiphat Banjongjit, Kamonchanok Metta, Khajohn Tiranathanagul, Yingyos Avihingsanon, Kearkiat Praditpornsilpa, Kriang Tungsanga, Somchai Eiam-Ong.

In hemodialysis (HD) patients, protein-energy wasting (PEW) is highly prevalent and firstly treated with oral nutritional supplements (ONS). The extent to which intradialytic parenteral nutrition (IDPN) contributes to improve PEW status in HD patients intolerable to ONS remains unclear. Maintenance PEW HD patients being unable to tolerate ONS adverse effects, and having spontaneous energy and protein intake of ≥ 20 kcal/kg/day and ≥ 0.8 g/kg/day, respectively were randomly assigned 1:1 into IDPN and control groups. In IDPN group, most concentrated 3-in-1, fish-oil based parenteral nutrition was infused during HD for 3 months. The control group received intensive dietary counselling once weekly for 3 months. Both groups were then followed for additional 3 months after intervention. A total of 38 patients were randomized (mean age 67.6 years). After 3 months, serum albumin was significantly higher in the IDPN (n = 18) compared with control group (from 3.5 ± 0.3 to 3.8 ± 0.2 vs from 3.6 ± 0.3 to 3.5 ± 0.3 g/dL, respectively, p = 0.01). Spontaneous dietary intake (p = 0.04), body weight (p = 0.01), and malnutrition inflammation score (MIS, p = 0.01) were improved in the IDPN, but not in the control group. Muscle mass, strength, serum prealbumin, interleukin-6, high sensitivity-c reactive protein, and acylated ghrelin were not significantly different but leptin levels increased in the control group after 3 months (p = 0.03). At 6 months, serum albumin in the IDPN group was persistently higher than baseline (p = 0.04). Neither volume overload nor uncontrolled hyperglycemia was found throughout the study. In conclusion, a 3-month IDPN supplementation demonstrated a significant increase in serum albumin, body weight, spontaneous oral intake, and MIS; and appeared to be superior to continuing intensive dietary counselling among HD patients intolerable to ONS. The impacts of IDPN therapy on clinical outcomes may require larger scale with longer period of study.

DOI: https://doi.org/10.1038/s41598-022-08726-8
Life Sci. 2022 Mar 09. pii: S0024-3205(22)00172-2. [Epub ahead of print]297 120472

Effect of running exercise on titanium dioxide (TiO2)-induced chronic arthritis and sarcopenia in mice. A titanium prosthesis loosening injury model study.

Philippe B Guirro, Jonathan H C Nunes, Paola S Cella, Poliana C Marinello, Felipe A Moura, Ricardo L N Matos, Ana Paula F R L Bracarense, Sérgio M Borghi, Waldiceu A Verri, Rafael Deminice.

   AIMS: This study aimed to investigate if titanium dioxide (TiO2) joint administration is a useful pre-clinical model to study sarcopenia-related chronic arthritis, and if exercise is a useful therapeutic approach against the pathogenesis of TiO2-induced arthritis and sarcopenia in mice.
MAIN METHODS: Two experiments were conducted. Firstly, 36 female Swiss mice were randomly divided into a control group (n = 12) and two groups who received intra-articular TiO2 injections of 0.3-mg (n = 12) and 3-mg (n = 12), respectively. Mice were euthanized 4 and 8 weeks after TiO2 injections. Based on data of the first experiment, mice were exposed to four groups: control (C, n = 10), exercised (Ex, n = 10), injected with 3-mg of TiO2 (TiO2, n = 10), and injected with 3-mg of TiO2 and exercised (TiO2 + Ex, n = 10) for a total of 8-weeks.
KEY FINDINGS: Eight-week of 3 mg of TiO2 joint administration promoted characteristics of chronic inflammation such as elevated histopathological score, inflammation, edema and pain. Hallmarks of sarcopenia were also observed such as muscle atrophy and loss of strength. Furthermore, voluntary exercise running reduced TiO2-induced chronic inflammation and pain, attenuating chronic arthritis-related muscle atrophy, strength loss and impairment of locomotion capacity. In addition, exercise was also able to prevent TiO2-induced collagen degradation, an important marker of functional and structural integrity loss of cartilage and chronic arthritis disease progression.
SIGNIFICANCE: TiO2 joint administration mimed titanium prosthesis release-induced joint chronic arthritis and sarcopenia-related chronic arthritis, disturbances that were attenuated by voluntary exercise.

Keywords:  Arthroplasty; Inflammatory pain; Muscle atrophy; Physical activity; Strength loss

DOI:  https://doi.org/10.1016/j.lfs.2022.120472
Front Nutr. 2022 ;9 828880

A Novel Application of Serum Creatinine and Cystatin C to Predict Sarcopenia in Advanced CKD.

Yu-Li Lin, Chih-Hsien Wang, I-Chen Chang, Bang-Gee Hsu.

  Sarcopenia is highly prevalent in patients with advanced chronic kidney disease (CKD), yet a reliable serum index has not been established. The product of serum creatinine and the estimated glomerular filtration rate based on cystatin C (Cr×eGFRcys) was recently proposed as a sarcopenia index (SI), approximately to 24-h filtered creatinine through the glomerulus. We aimed to evaluate the diagnostic validity of the novel SI in advanced CKD. In 297 patients with non-dialysis stage 3b-5 CKD, aged 68.8 ± 12.9 years, the total skeletal muscle mass (SMM), handgrip strength (HGS), and usual gait speed were assessed. Sarcopenia was defined based on the Asian Working Group for Sarcopenia 2019 consensus update. The prevalence of sarcopenia in this cohort was 20.2%. The SI correlated moderately with SMM (r = 0.503, P < 0.001), HGS (r = 0.508, P < 0.001), and gait speed (r = 0.381, P < 0.001); the independency of the SI with three muscle metrics was confirmed after extensive adjustment. For sarcopenia prediction, the SI had acceptable discriminative powers in males [area under the receiver operating characteristic curve (AUC) 0.646, 95% confidence interval (CI) 0.569-0.718] and females (AUC 0.754, 95% CI 0.670-0.826). In males, the best cut-off was 53.9, which provided 71.1% sensitivity, 58.0% specificity, 32.9% positive predictive value (PPV), and 87.4% negative predictive value (NPV); in females, the best cut-off was 45.8, which provided 81.8% sensitivity, 62.3% specificity, 31.0% PPV, and 94.3% NPV. In conclusion, Cr×eGFRcys could be served as a surrogate marker for sarcopenia and may be helpful for sarcopenia screening in advanced CKD. Further studies are needed to expand our investigation.

Keywords:  chronic kidney disease; creatinine; cystatin C; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.3389/fnut.2022.828880
Toxicol Mech Methods. 2022 Mar 17. 1-13

Defective mitophagy and induction of apoptosis by the depleted levels of PINK1 and parkin in Pb and β-amyloid peptide induced toxicity.

Lakshmi Jaya Madhuri B, Neelima Ayyalasomayajula, Lokesh Murumulla, Prasanna Kumar Dixit, Challa Suresh.

  Exposure to lead (Pb), an environmental pollutant, is closely associated with the development of neurodegenerative disorders through oxidative stress induction and alterations in mitochondrial function. Damaged mitochondria could be one of the reasons for the progression of Alzheimer's Disease (AD). Mitophagy is vital in keeping the cell healthy. To know its role in Pb-induced AD, we investigated the PINK1/parkin dependent pathway by studying specific mitophagy marker proteins such as PINK1 and parkin in differentiated SH-SY5Y cells. Our data have indicated a significant reduction in the levels of PINK1 and parkin in cells exposed to Pb and β-amyloid peptides, both Aβ (25-35) and Aβ (1-40) individually and in different combinations, resulting in defective mitophagy. Also, the study unravels the status of mitochondrial permeability transition pore (MPTP), mitochondrial mass, mitochondrial membrane potential (MMP) and mitochondrial ROS production in cells treated with individual and different combination of Pb and Aβ peptides. An increase in mitochondrial ROS production, enhanced MPTP opening, depolarization of membrane potential and reduced mitochondrial mass in the exposed groups were observed. Also, in the present study, we found that Pb and β-amyloid peptides could trigger apoptosis by activating the Bak protein, which releases the cytochrome c from mitochondria through MPTP that further activates the AIF (apoptosis inducing factor) and caspase-3 proteins in the cytosol. The above findings reveal the potential role of mechanisms like PINK1/parkin mediated mitophagy and dysfunctional mitochondria mediated apoptosis in Pb induced neurotoxicity.

Keywords:  Alzheimer’s disease; Lead toxicity; Mitophagy; PINK1/parkin; apoptosis; β-Amyloid peptide

DOI:  https://doi.org/10.1080/15376516.2022.2054749