bims-aucach 2022-03-13 papers

bims-aucach

Biomed News

on Autophagy and cachexia

Issue of 2022–03–13
twelve papers selected by
Kleiton Silva, Rowan University

Gut microbes and muscle function: can probiotics make our muscles stronger?
Exercise and Training Regulation of Autophagy Markers in Human and Rat Skeletal Muscle.
Coordination of mitochondrial and lysosomal homeostasis mitigates inflammation and muscle atrophy during aging.
Hypothalamic-pituitary-adrenal axis activation and glucocorticoid-responsive gene expression in skeletal muscle and liver of Apc mice.
Exercise Therapy for People With Sarcopenic Obesity: Myokines and Adipokines as Effective Actors.
Impact of high-intensity interval training with or without l-citrulline on physical performance, skeletal muscle, and adipose tissue in obese older adults.
From the Bench to the Bedside: Branched Amino Acid and Micronutrient Strategies to Improve Mitochondrial Dysfunction Leading to Sarcopenia.
Role of Mitochondrial Stress Response in Cancer Progression.
Musculoskeletal Aging and Sarcopenia in the Elderly.
The impact of breast cancer on fears of exercise and exercise identity.
Maintaining Golgi Homeostasis: A Balancing Act of Two Proteolytic Pathways.
Golgi quality control and autophagy.

J Cachexia Sarcopenia Muscle. 2022 Mar 12.

Gut microbes and muscle function: can probiotics make our muscles stronger?

Muriel Giron, Muriel Thomas, Dominique Dardevet, Christophe Chassard, Isabelle Savary-Auzeloux.

  Evidence suggests that gut microbiota composition and diversity can be a determinant of skeletal muscle metabolism and functionality. This is true in catabolic (sarcopenia and cachexia) or anabolic (exercise or in athletes) situations. As gut microbiota is known to be causal in the development and worsening of metabolic dysregulation phenotypes such as obesity or insulin resistance, it can regulate, at least partially, skeletal muscle mass and function. Skeletal muscles are physiologically far from the gut. Signals generated by the gut due to its interaction with the gut microbiome (microbial metabolites, gut peptides, lipopolysaccharides, and interleukins) constitute links between gut microbiota activity and skeletal muscle and regulate muscle functionality via modulation of systemic/tissue inflammation as well as insulin sensitivity. The probiotics able to limit sarcopenia and cachexia or promote health performances in rodents are mainly lactic acid bacteria and bifidobacteria. In humans, the same bacteria have been tested, but the scarcity of the studies, the variability of the populations, and the difficulty to measure accurately and with high reproducibility muscle mass and function have not allowed to highlight specific strains able to optimize muscle mass and function. Further studies are required on more defined population, in order to design personalized nutrition. For elderly, testing the efficiency of probiotics according to the degree of frailty, nutritional state, or degree of sarcopenia before supplementation is essential. For exercise, selection of probiotics capable to be efficient in recreational and/or elite athletes, resistance, and/or endurance exercise would also require further attention. Ultimately, a combination of strategies capable to optimize muscle functionality, including bacteria (new microbes, bacterial ecosystems, or mix, more prone to colonize a specific gut ecosystem) associated with prebiotics and other 'traditional' supplements known to stimulate muscle anabolism (e.g. proteins), could be the best way to preserve muscle functionality in healthy individuals at all ages or patients.

Keywords:  Ageing; Athlete; Cachexia; Exercise; Probiotic; Sarcopenia; Skeletal muscle

DOI:  https://doi.org/10.1002/jcsm.12964
Int J Mol Sci. 2022 Feb 27. pii: 2619. [Epub ahead of print]23(5):

Exercise and Training Regulation of Autophagy Markers in Human and Rat Skeletal Muscle.

Javier Botella, Nicholas A Jamnick, Cesare Granata, Amanda J Genders, Enrico Perri, Tamim Jabar, Andrew Garnham, Michael Lazarou, David J Bishop.

  Autophagy is a key intracellular mechanism by which cells degrade old or dysfunctional proteins and organelles. In skeletal muscle, evidence suggests that exercise increases autophagosome content and autophagy flux. However, the exercise-induced response seems to differ between rodents and humans, and little is known about how different exercise prescription parameters may affect these results. The present study utilised skeletal muscle samples obtained from four different experimental studies using rats and humans. Here, we show that, following exercise, in the soleus muscle of Wistar rats, there is an increase in LC3B-I protein levels immediately after exercise (+109%), and a subsequent increase in LC3B-II protein levels 3 h into the recovery (+97%), despite no change in Map1lc3b mRNA levels. Conversely, in human skeletal muscle, there is an immediate exercise-induced decrease in LC3B-II protein levels (-24%), independent of whether exercise is performed below or above the maximal lactate steady state, which returns to baseline 3.5 h following recovery, while no change in LC3B-I protein levels or MAP1LC3B mRNA levels is observed. SQSTM1/p62 protein and mRNA levels did not change in either rats or humans following exercise. By employing an ex vivo autophagy flux assay previously used in rodents we demonstrate that the exercise-induced decrease in LC3B-II protein levels in humans does not reflect a decreased autophagy flux. Instead, effect size analyses suggest a modest-to-large increase in autophagy flux following exercise that lasts up to 24 h. Our findings suggest that exercise-induced changes in autophagosome content markers differ between rodents and humans, and that exercise-induced decreases in LC3B-II protein levels do not reflect autophagy flux level.

Keywords:  LC3; autophagy; exercise; skeletal muscle

DOI:  https://doi.org/10.3390/ijms23052619
Aging Cell. 2022 Mar 09. e13583

Coordination of mitochondrial and lysosomal homeostasis mitigates inflammation and muscle atrophy during aging.

Andrea Irazoki, Marta Martinez-Vicente, Pilar Aparicio, Cecilia Aris, Esmaeil Alibakhshi, Maria Rubio-Valera, Juan Castellanos, Luis Lores, Manuel Palacín, Anna Gumà, Antonio Zorzano, David Sebastián.

  Sarcopenia is one of the main factors contributing to the disability of aged people. Among the possible molecular determinants of sarcopenia, increasing evidences suggest that chronic inflammation contributes to its development. However, a key unresolved question is the nature of the factors that drive inflammation during aging and that participate in the development of sarcopenia. In this regard, mitochondrial dysfunction and alterations in mitophagy induce inflammatory responses in a wide range of cells and tissues. However, whether accumulation of damaged mitochondria (MIT) in muscle could trigger inflammation in the context of aging is still unknown. Here, we demonstrate that BCL2 interacting protein 3 (BNIP3) plays a key role in the control of mitochondrial and lysosomal homeostasis, and mitigates muscle inflammation and atrophy during aging. We show that muscle BNIP3 expression increases during aging in mice and in some humans. BNIP3 deficiency alters mitochondrial function, decreases mitophagic flux and, surprisingly, induces lysosomal dysfunction, leading to an upregulation of Toll-like receptor 9 (TLR9)-dependent inflammation and activation of the NLRP3 (nucleotide-binding oligomerization domain (NOD)-, leucine-rich repeat (LRR)-, and pyrin domain-containing protein 3) inflammasome in muscle cells and mouse muscle. Importantly, downregulation of muscle BNIP3 in aged mice exacerbates inflammation and muscle atrophy, and high BNIP3 expression in aged human subjects associates with a low inflammatory profile, suggesting a protective role for BNIP3 against age-induced muscle inflammation in mice and humans. Taken together, our data allow us to propose a new adaptive mechanism involving the mitophagy protein BNIP3, which links mitochondrial and lysosomal homeostasis with inflammation and is key to maintaining muscle health during aging.

Keywords:  aging; inflammation; lysosome; mitochondria; mitophagy; muscle

DOI:  https://doi.org/10.1111/acel.13583
J Cachexia Sarcopenia Muscle. 2022 Mar 11.

Hypothalamic-pituitary-adrenal axis activation and glucocorticoid-responsive gene expression in skeletal muscle and liver of Apc mice.

Agnès Martin, Josiane Castells, Valentine Allibert, Andréa Emerit, Cindy Zolotoff, Victoire Cardot-Ruffino, Yann S Gallot, Barbara Vernus, Véronique Chauvet, Laurent Bartholin, Laurent Schaeffer, Anne-Cécile Durieux, Christophe Hourdé, François B Favier, Laetitia Mazelin, Damien Freyssenet.

   BACKGROUND: Cancer patients at advanced stages experience a severe depletion of skeletal muscle compartment together with a decrease in muscle function, known as cancer cachexia. Cachexia contributes to reducing quality of life, treatment efficiency, and lifespan of cancer patients. However, the systemic nature of the syndrome is poorly documented. Here, we hypothesize that glucocorticoids would be important systemic mediators of cancer cachexia.
METHODS: To explore the role of glucocorticoids during cancer cachexia, biomolecular analyses were performed on several tissues (adrenal glands, blood, hypothalamus, liver, and skeletal muscle) collected from ApcMin/+ male mice, a mouse model of intestine and colon cancer, aged of 13 and 23 weeks, and compared with wild type age-matched C57BL/6J littermates.
RESULTS: Twenty-three-week-old Apc mice recapitulated important features of cancer cachexia including body weight loss (-16%, P < 0.0001), muscle atrophy (gastrocnemius muscle: -53%, P < 0.0001), and weakness (-50% in tibialis anterior muscle force, P < 0.0001), increased expression of atrogens (7-fold increase in MuRF1 transcript level, P < 0.0001) and down-regulation of Akt-mTOR pathway (3.3-fold increase in 4EBP1 protein content, P < 0.0001), together with a marked transcriptional rewiring of hepatic metabolism toward an increased expression of gluconeogenic genes (Pcx: +90%, Pck1: +85%), and decreased expression of glycolytic (Slc2a2: -40%, Gk: -30%, Pklr: -60%), ketogenic (Hmgcs2: -55%, Bdh1: -80%), lipolytic/fatty oxidation (Lipe: -50%, Mgll: -60%, Cpt2: -60%, Hadh: -30%), and lipogenic (Acly: -30%, Acacb: -70%, Fasn: -45%) genes. The hypothalamic pituitary-adrenal axis was activated, as evidenced by the increase in the transcript levels of genes encoding corticotropin-releasing hormone in the hypothalamus (2-fold increase, P < 0.01), adrenocorticotropic hormone receptor (3.4-fold increase, P < 0.001), and steroid biosynthesis enzymes (Cyp21a1, P < 0.0001, and Cyp11b1, P < 0.01) in the adrenal glands, as well as by the increase in corticosterone level in the serum (+73%, P < 0.05), skeletal muscle (+17%, P < 0.001), and liver (+24%, P < 0.05) of cachectic 23-week-old Apc mice. A comparative transcriptional analysis with dexamethasone-treated C57BL/6J mice indicated that the activation of the hypothalamic-pituitary-adrenal axis in 23-week-old ApcMin/+ mice was significantly associated with the transcription of glucocorticoid-responsive genes in skeletal muscle (P < 0.05) and liver (P < 0.001). The transcriptional regulation of glucocorticoid-responsive genes was also observed in the gastrocnemius muscle of Lewis lung carcinoma tumour-bearing mice and in KPC mice (tibialis anterior muscle and liver).
CONCLUSIONS: These findings highlight the role of the hypothalamic-pituitary-adrenal-glucocorticoid pathway in the transcriptional regulation of skeletal muscle catabolism and hepatic metabolism during cancer cachexia. They also provide the paradigm for the design of new therapeutic strategies.

Keywords:  Cancer cachexia; Glucocorticoid; Hypothalamic-pituitary-adrenal axis; Liver; Metabolism; Skeletal muscle

DOI:  https://doi.org/10.1002/jcsm.12939
Front Endocrinol (Lausanne). 2022 ;13 811751

Exercise Therapy for People With Sarcopenic Obesity: Myokines and Adipokines as Effective Actors.

Hamed Alizadeh Pahlavani.

  Sarcopenic obesity is defined as a multifactorial disease in aging with decreased body muscle, decreased muscle strength, decreased independence, increased fat mass, due to decreased physical activity, changes in adipokines and myokines, and decreased satellite cells. People with sarcopenic obesity cause harmful changes in myokines and adipokines. These changes are due to a decrease interleukin-10 (IL-10), interleukin-15 (IL-15), insulin-like growth factor hormone (IGF-1), irisin, leukemia inhibitory factor (LIF), fibroblast growth factor-21 (FGF-21), adiponectin, and apelin. While factors such as myostatin, leptin, interleukin-6 (IL-6), interleukin-8 (IL-8), and resistin increase. The consequences of these changes are an increase in inflammatory factors, increased degradation of muscle proteins, increased fat mass, and decreased muscle tissue, which exacerbates sarcopenia obesity. In contrast, exercise, especially strength training, reverses this process, which includes increasing muscle protein synthesis, increasing myogenesis, increasing mitochondrial biogenesis, increasing brown fat, reducing white fat, reducing inflammatory factors, and reducing muscle atrophy. Since some people with chronic diseases are not able to do high-intensity strength training, exercises with blood flow restriction (BFR) are newly recommended. Numerous studies have shown that low-intensity BFR training produces the same increase in hypertrophy and muscle strength such as high-intensity strength training. Therefore, it seems that exercise interventions with BFR can be an effective way to prevent the exacerbation of sarcopenia obesity. However, due to limited studies on adipokines and exercises with BFR in people with sarcopenic obesity, more research is needed.

Keywords:  adipokines; exercise; myokines; obesity; sarcopenia

DOI:  https://doi.org/10.3389/fendo.2022.811751
J Cachexia Sarcopenia Muscle. 2022 Mar 07.

Impact of high-intensity interval training with or without l-citrulline on physical performance, skeletal muscle, and adipose tissue in obese older adults.

Vincent Marcangeli, Layale Youssef, Maude Dulac, Livia P Carvalho, Guy Hajj-Boutros, Olivier Reynaud, Bénédicte Guegan, Fanny Buckinx, Pierrette Gaudreau, José A Morais, Pascale Mauriège, Philippe Noirez, Mylène Aubertin-Leheudre, Gilles Gouspillou.

   BACKGROUND: Aging is associated with a progressive decline in skeletal muscle mass and strength as well as an increase in adiposity. These changes may have devastating impact on the quality of life of older adults. Mitochondrial dysfunctions have been implicated in aging-related and obesity-related deterioration of muscle function. Impairments in mitochondrial quality control processes (biogenesis, fusion, fission, and mitophagy) may underlie this accumulation of mitochondrial dysfunction. High-intensity interval training (HIIT) was shown to improve muscle and mitochondrial function in healthy young and old adults and to improve body composition in obese older adults. Recent studies also positioned citrulline (CIT) supplementation as a promising intervention to counter obesity-related and aging-related muscle dysfunction. In the present study, our objectives were to assess whether HIIT, alone or with CIT, improves muscle function, functional capacities, adipose tissue gene expression, and mitochondrial quality control processes in obese older adults.
METHODS: Eighty-one-old and obese participants underwent a 12 week HIIT with or without CIT on an elliptical trainer [HIIT-CIT: 20 men/25 women, 67.2 ± 5.0 years; HIIT-placebo (PLA): 18 men/18 women, 68.1 ± 4.1 years]. Handgrip and quadriceps strength, lower limb muscle power, body composition, waist circumference, and functional capacities were assessed pre and post intervention. Vastus lateralis muscle biopsies were performed in a subset of participants to quantify markers of mitochondrial content (TOM20 and OXPHOS subunits), biogenesis (TFAM), fusion (MFN1&2, OPA1), fission (DRP1), and mitophagy (Parkin). Subcutaneous abdominal adipose tissue biopsies were also performed to assess the expression of genes involved in lipid metabolism.
RESULTS: HIIT-PLA and HIIT-CIT displayed improvements in functional capacities (P < 0.05), total (mean ± SD: HIIT-PLA: +1.27 ± 3.19%, HIIT-CIT: +1.05 ± 2.91%, P < 0.05) and leg lean mass (HIIT-PLA: +1.62 ± 3.85%, HIIT-CIT: +1.28 ± 4.82%, P < 0.05), waist circumference (HIIT-PLA: -2.2 ± 2.9 cm, HIIT-CIT: -2.6 ± 2.5 cm, P < 0.05), and muscle power (HIIT-PLA: +15.81 ± 18.02%, HIIT-CIT: +14.62 ± 20.02%, P < 0.05). Only HIIT-CIT decreased fat mass (-1.04 ± 2.42%, P < 0.05) and increased handgrip and quadriceps strength (+4.28 ± 9.36% and +10.32 ± 14.38%, respectively, P < 0.05). Both groups increased markers of muscle mitochondrial content, mitochondrial fusion, and mitophagy (P < 0.05). Only HIIT-CIT decreased the expression of the lipid droplet-associated protein CIDEA (P < 0.001).
CONCLUSIONS: High-intensity interval training is effective in improving functional capacities, lean mass, muscle power, and waist circumference in obese older adults. HIIT also increases markers of mitochondrial biogenesis, mitochondrial fusion, and mitophagy. Importantly, adding CIT to HIIT results in a greater increase in muscle strength and a significant decrease in fat mass. The present study therefore positions HIIT combined with CIT as an effective intervention to improve the health status of obese older adults.

Keywords:  Aging; Exercise; Gene expression; High-intensity interval training; Mitochondrial dynamics; Mitochondrial quality control; Mitophagy; Mobility; Nutrition; Obesity; Sarcopenia

DOI:  https://doi.org/10.1002/jcsm.12955
Nutrients. 2022 Jan 22. pii: 483. [Epub ahead of print]14(3):

From the Bench to the Bedside: Branched Amino Acid and Micronutrient Strategies to Improve Mitochondrial Dysfunction Leading to Sarcopenia.

Mario Romani, Mette M Berger, Patrizia D'Amelio.

  With extended life expectancy, the older population is constantly increasing, and consequently, so too is the prevalence of age-related disorders. Sarcopenia, the pathological age-related loss of muscle mass and function; and malnutrition, the imbalance in nutrient intake and resultant energy production, are both commonly occurring conditions in old adults. Altered nutrition plays a crucial role in the onset of sarcopenia, and both these disorders are associated with detrimental consequences for patients (e.g., frailty, morbidity, and mortality) and society (e.g., healthcare costs). Importantly, sarcopenia and malnutrition also share critical molecular alterations, such as mitochondrial dysfunction, increased oxidative stress, and a chronic state of low grade and sterile inflammation, defined as inflammageing. Given the connection between malnutrition and sarcopenia, nutritional interventions capable of affecting mitochondrial health and correcting inflammageing are emerging as possible strategies to target sarcopenia. Here, we discuss mitochondrial dysfunction, oxidative stress, and inflammageing as key features leading to sarcopenia. Moreover, we examine the effects of some branched amino acids, omega-3 PUFA, and selected micronutrients on these pathways, and their potential role in modulating sarcopenia, warranting further clinical investigation.

Keywords:  branched-chain amino acids (BCAAs); inflammageing; malnutrition; mitochondria; n-3 PUFA; sarcopenia; selenium; senescence; vitamin D; zinc

DOI:  https://doi.org/10.3390/nu14030483
Cells. 2022 Feb 23. pii: 771. [Epub ahead of print]11(5):

Role of Mitochondrial Stress Response in Cancer Progression.

Yu Geon Lee, Do Hong Park, Young Chan Chae.

  Mitochondria are subcellular organelles that are a hub for key biological processes, such as bioenergetic, biosynthetic, and signaling functions. Mitochondria are implicated in all oncogenic processes, from malignant transformation to metastasis and resistance to chemotherapeutics. The harsh tumor environment constantly exposes cancer cells to cytotoxic stressors, such as nutrient starvation, low oxygen, and oxidative stress. Excessive or prolonged exposure to these stressors can cause irreversible mitochondrial damage, leading to cell death. To survive hostile microenvironments that perturb mitochondrial function, cancer cells activate a stress response to maintain mitochondrial protein and genome integrity. This adaptive mechanism, which is closely linked to mitochondrial function, enables rapid adjustment and survival in harsh environmental conditions encountered during tumor dissemination, thereby promoting cancer progression. In this review, we describe how the mitochondria stress response contributes to the acquisition of typical malignant traits and highlight the potential of targeting the mitochondrial stress response as an anti-cancer therapeutic strategy.

Keywords:  mitochondrial dynamics; mitochondrial protein quality control; mitochondrial stress response; mitophagy; mtDNA

DOI:  https://doi.org/10.3390/cells11050771
Int J Mol Sci. 2022 Mar 04. pii: 2808. [Epub ahead of print]23(5):

Musculoskeletal Aging and Sarcopenia in the Elderly.

Emanuele Marzetti.

The loss of skeletal muscle mass and strength/function, referred to as sarcopenia, is a pervasive feature of aging [...].

DOI: https://doi.org/10.3390/ijms23052808
Patient Educ Couns. 2022 Mar 04. pii: S0738-3991(22)00095-7. [Epub ahead of print]

The impact of breast cancer on fears of exercise and exercise identity.

James Murray, Rebecca Perry, Emma Pontifex, Sudarsha Selva-Nayagam, Eva Bezak, Hunter Bennett.

   OBJECTIVES: Low exercise adherence is common amongst breast cancer (BC) patients. This study aimed to understand BC patients exercise identity and fears of exercise to identify barriers to exercise participation.
METHODS: Women (18 years plus) currently undergoing, or completed (in remission), chemotherapy for BC, and women (18 years plus) with no cancer history completed three validated questionnaires: Exercise Identity Scale (EI), Exercise Fear Avoidance Scale (EFAS) and Fear of Physical Activity/Exercise Scale - Breast Cancer.
RESULTS: 86 women were included (BC: n = 51 - non-cancer: n = 35). There were no significant differences between groups when comparing overall EI (p = 0.240; d=0.127) and EFAS (p = 0.060; d=0.203) scores. BC reported significantly higher scores on specific questions related to fear during exercise (EFAS 2,3, and 5; p = <0.005). Associations were observed between EI and EFAS questionnaire scores in BC (r = -0.342; p = 0.014), and EI scores and exercise levels in both groups (BC, r = 0.527; p = <0.001; non-cancer, r = 0.639; p = <0.001).
CONCLUSION: Results suggest women with BC may have specific concerns and fears of exercise compared to age-matched controls. Education may mitigate fears, increase exercise identity, and promote exercise uptake.
PRACTICAL IMPLICATIONS: Education provided by clinicians at BC diagnosis regarding the benefits and safety of exercise may help mitigate fear and promote exercise identity.

Keywords:  Breast carcinoma; Physical activity; Psychosocial; Questionnaires

DOI:  https://doi.org/10.1016/j.pec.2022.03.002
Cells. 2022 Feb 23. pii: 780. [Epub ahead of print]11(5):

Maintaining Golgi Homeostasis: A Balancing Act of Two Proteolytic Pathways.

Ron Benyair, Avital Eisenberg-Lerner, Yifat Merbl.

  The Golgi apparatus is a central hub for cellular protein trafficking and signaling. Golgi structure and function is tightly coupled and undergoes dynamic changes in health and disease. A crucial requirement for maintaining Golgi homeostasis is the ability of the Golgi to target aberrant, misfolded, or otherwise unwanted proteins to degradation. Recent studies have revealed that the Golgi apparatus may degrade such proteins through autophagy, retrograde trafficking to the ER for ER-associated degradation (ERAD), and locally, through Golgi apparatus-related degradation (GARD). Here, we review recent discoveries in these mechanisms, highlighting the role of the Golgi in maintaining cellular homeostasis.

Keywords:  EGAD; GARD; GOMED; Golgi; autophagy; proteasomal degradation; proteostasis

DOI:  https://doi.org/10.3390/cells11050780
IUBMB Life. 2022 Mar 10.

Golgi quality control and autophagy.

Hsiang-Yi Chang, Wei Yuan Yang.

  Organelles can easily be disrupted by intracellular and extracellular factors. Studies on ER and mitochondria indicate that a wide range of responses are elicited upon organelle disruption. One response thought to be of particular importance is autophagy. Cells can target entire organelles into autophagosomes for removal. This wholesale nature makes autophagy a robust means for eliminating compromised organelles. Recently, it was demonstrated that the Golgi apparatus is a substrate of autophagy. On the other hand, various reports have shown that components traffic away from the Golgi for elimination in an autophagosome-independent manner when the Golgi apparatus is stressed. Future studies will reveal how these different pieces of machinery coordinate to drive Golgi degradation. Quantitative measurements will be needed to determine how much autophagy contributes to the maintenance of the Golgi apparatus.

Keywords:  Golgi apparatus; Golgi fragmentation; Golgi-derived vesicles; autophagy; biogenesis; proteasome

DOI:  https://doi.org/10.1002/iub.2611