scholarly journals Hyperphosphatemia increases inflammation to exacerbate anemia and skeletal muscle wasting independently of FGF23-FGFR4 signaling

2021 ◽  
Author(s):  
Brian Czaya ◽  
Kylie Heitman ◽  
Isaac Campos ◽  
Christopher Yanucil ◽  
Dominik Kentrup ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Wasting ◽  
Genetic Disorders ◽  
Fibroblast Growth Factor 23 ◽  
Kidney Injury ◽  
Hepcidin Expression ◽  
Phosphate Intake ◽  
Skeletal Muscle Wasting ◽  
High Phosphate

Elevations in plasma phosphate concentrations (hyperphosphatemia) occur in chronic kidney disease (CKD), in certain genetic disorders, and following the intake of a phosphate-rich diet. Whether hyperphosphatemia and/or associated changes in metabolic regulators, including elevations of fibroblast growth factor 23 (FGF23) directly contribute to specific complications of CKD is uncertain. Here we report that similar to patients with CKD, mice with adenine-induced CKD develop inflammation, anemia and skeletal muscle wasting. These complications are also observed in mice fed high phosphate diet even without CKD. Ablation of pathologic FGF23-FGFR4 signaling did not protect mice on an increased phosphate diet or mice with adenine-induced CKD from these sequelae. However, low phosphate diet ameliorated anemia and skeletal muscle wasting in a genetic mouse model of CKD. Our mechanistic in vitro studies indicate that phosphate elevations induce inflammatory signaling and increase hepcidin expression in hepatocytes, a potential causative link between hyperphosphatemia, anemia and skeletal muscle dysfunction. Our study suggests that high phosphate intake, as caused by the consumption of processed food, may have harmful effects irrespective of pre-existing kidney injury, supporting not only the clinical utility of treating hyperphosphatemia in CKD patients but also arguing for limiting phosphate intake in healthy individuals.

scholarly journals Ovarian cancer ascites induces skeletal muscle wasting in vitro and reflects sarcopenia in patients

2021 ◽  
Author(s):  
Jorne Ubachs ◽  
Wouter R.P.H. Worp ◽  
Rianne D.W. Vaes ◽  
Kenneth Pasmans ◽  
Ramon C. Langen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Skeletal Muscle ◽  
Muscle Wasting ◽  
Skeletal Muscle Wasting

scholarly journals SUN-140 TMEPAI Inhibits SMAD 2/3 Mediated Muscle Wasting

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Swati Kharoud ◽  
Kelly Louise Walton ◽  
Adam Hagg ◽  
Georgia Goodchild ◽  
Justin Chen ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Gene Delivery ◽  
Muscle Mass ◽  
Muscle Wasting ◽  
Activin A ◽  
Viral Gene ◽  
Soluble Receptors ◽  
Skeletal Muscle Wasting ◽  
Viral Gene Delivery

Abstract Inhibition of myostatin and activin activity using ligand traps, such as soluble receptors, follistatin and propeptides, can markedly increase skeletal muscle mass in healthy mice and ameliorate wasting in models of cancer cachexia and muscular dystrophy. Though effective, clinical translation of these approaches has been hindered by off-target effects. Toward the goal of developing tissue-specific myostatin/activin interventions, we explored the ability of transmembrane prostate androgen-induced (TMEPAI) to promote growth of skeletal muscle. TMEPAI, a transcriptional target of activin in muscle, is a known inhibitor of TGF-β1-mediated SMAD 2/3 signalling. In this study we show that TMEPAI also blocks activin A, activin B, myostatin and GDF-11 in vitro activity. Adeno-associated viral (AAV) gene delivery of TMEPAI into healthy mice increased local muscle mass by as much as 30%. Increased muscle mass was attributed to hypertrophy of fibres in TMEPAI-expressing muscles, and was coincident with an upregulation in markers of protein synthesis (pAkt, pMTOR, p70S6K). The ability of TMEPAI to block activation of the canonical activin/myostatin-SMAD 2/3 axis, was demonstrated by co-injecting AAV6:activin A and AAV6:TMEPAI into healthy mice. In this setting, TMEPAI blocked activin-induced phosphorylation of SMAD3 and associated skeletal muscle wasting. Finally, delivery of AAV6:TMEPAI into tibialis anterior muscles of mice bearing C26 tumours prevented muscle atrophy normally associated with this model. The results support that viral gene delivery of TMEPAI can effectively increase muscle mass via inactivation of the activin/myostatin-SMAD 2/3 pathway.

Low magnesium diet aggravates phosphate-induced kidney injury

2018 ◽  
Vol 34 (8) ◽  
pp. 1310-1319 ◽  
Author(s):  
Yusuke Sakaguchi ◽  
Takayuki Hamano ◽  
Isao Matsui ◽  
Tatsufumi Oka ◽  
Satoshi Yamaguchi ◽  
...  
Keyword(s):  
Interstitial Fibrosis ◽  
Fibroblast Growth Factor 23 ◽  
Kidney Injury ◽  
Diet Group ◽  
Low Magnesium ◽  
Phosphate Excretion ◽  
Renal Histology ◽  
High Phosphate

Abstract Background Magnesium is known to protect against phosphate-induced tubular cell injuries in vitro. We investigated in vivo effects of magnesium on kidney injuries and phosphate metabolism in mice exposed to a high phosphate diet. Methods Heminephrectomized mice were maintained on a high phosphate/normal magnesium diet or a high phosphate/low magnesium diet for 6 weeks. We compared renal histology, phosphaturic hormones and renal α-Klotho expression between the two diet groups. Results High phosphate diet–induced tubular injuries and interstitial fibrosis were remarkably aggravated by the low-magnesium diet. At 1 week after high phosphate feeding when serum creatinine levels were similar between the two groups, the low magnesium diet suppressed not only fecal phosphate excretion but also urinary phosphate excretion, resulting in increased serum phosphate levels. Parathyroid hormone (PTH) levels were not appropriately elevated in the low magnesium diet group despite lower 1,25-dihydroxyvitamin D and serum calcium levels compared with the normal magnesium diet group. Although fibroblast growth factor 23 (FGF23) levels were lower in the low magnesium diet group, calcitriol-induced upregulation of FGF23 could not restore the impaired urinary phosphate excretion. The low magnesium diet markedly downregulated α-Klotho expression in the kidney. This downregulation of α-Klotho occurred even when mice were fed the low phosphate diet. Conclusions A low magnesium diet aggravated high phosphate diet–induced kidney injuries. Impaired PTH secretion and downregulation of renal α-Klotho were likely to be involved in the blunted urinary phosphate excretion by the low magnesium diet. Increasing dietary magnesium may be useful to attenuate phosphate-induced kidney injury.

Myostatin promotes the wasting of human myoblast cultures through promoting ubiquitin-proteasome pathway-mediated loss of sarcomeric proteins

2011 ◽  
Vol 301 (6) ◽  
pp. C1316-C1324 ◽  
Author(s):  
Sudarsanareddy Lokireddy ◽  
Vincent Mouly ◽  
Gillian Butler-Browne ◽  
Peter D. Gluckman ◽  
Mridula Sharma ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Human Skeletal Muscle ◽  
Muscle Wasting ◽  
Negative Regulator ◽  
Potent Inducer ◽  
Ubiquitin Proteasome Pathway ◽  
Skeletal Muscle Wasting ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Myostatin is a negative regulator of skeletal muscle growth and in fact acts as a potent inducer of “cachectic-like” muscle wasting in mice. The mechanism of action of myostatin in promoting muscle wasting has been predominantly studied in murine models. Despite numerous reports linking elevated levels of myostatin to human skeletal muscle wasting conditions, little is currently known about the signaling mechanism(s) through which myostatin promotes human skeletal muscle wasting. Therefore, in this present study we describe in further detail the mechanisms behind myostatin regulation of human skeletal muscle wasting using an in vitro human primary myotube atrophy model. Treatment of human myotube populations with myostatin promoted dramatic myotubular atrophy. Mechanistically, myostatin-induced myotube atrophy resulted in reduced p-AKT concomitant with the accumulation of active dephosphorylated Forkhead Box-O (FOXO1) and FOXO3. We further show that addition of myostatin results in enhanced activation of atrogin-1 and muscle-specific RING finger protein 1 (MURF1) and reduced expression of both myosin light chain (MYL) and myosin heavy chain (MYH). In addition, we found that myostatin-induced loss of MYL and MYH proteins is dependent on the activity of the proteasome and mediated via SMAD3-dependent regulation of FOXO1 and atrogin-1. Therefore, these data suggest that the mechanism through which myostatin promotes muscle wasting is very well conserved between species, and that myostatin-induced human myotube atrophy is mediated through inhibition of insulin-like growth factor (IGF)/phosphoinositide 3-kinase (PI3-K)/AKT signaling and enhanced activation of the ubiquitin-proteasome pathway and elevated protein degradation.

scholarly journals Skeletal Muscle Resident Progenitor Cells Coexpress Mesenchymal and Myogenic Markers and Are Not Affected by Chronic Heart Failure-Induced Dysregulations

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
R. I. Dmitrieva ◽  
T. A. Lelyavina ◽  
M. Y. Komarova ◽  
V. L. Galenko ◽  
O. A. Ivanova ◽  
...  
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Progenitor Cells ◽  
Functional Properties ◽  
Muscle Wasting ◽  
Regeneration Potential ◽  
Metabolic Alterations ◽  
Skeletal Muscle Wasting ◽  
Myogenic Markers

Background and Purpose. In heart failure (HF), metabolic alterations induce skeletal muscle wasting and decrease of exercise capacity and quality of life. The activation of skeletal muscle regeneration potential is a prospective strategy to reduce muscle wasting; therefore, the aim of this project was to determine if functional properties of skeletal muscle mesenchymal progenitor cells (SM-MPC) were affected by HF-induced functional and metabolic dysregulations. Methods. Gastrocnemius muscle biopsy samples were obtained from 3 healthy donors (HD) and 12 HF patients to purify mRNA for further analysis and to isolate SM-MPC. Cells were expanded in vitro and characterized by immunocytochemistry and flow cytometry for expression of mesenchymal (CD105/CD73/CD166/CD146/CD140b/CD140a/VIM) and myogenic (Myf5/CD56/MyoG) markers. Cells were induced to differentiate and were then analyzed by immunostaining and Q-PCR to verify the efficiency of differentiation. The expression of genes that control muscle metabolism and development was compared for HD/HF patients in both muscle biopsy and in vitro-differentiated myotubes. Results. The upregulation of MYH3/MYH8/Myf6 detected in HF skeletal muscle along with metabolic alterations indicates chronic pathological activation of the muscle developmental program. SM-MPC isolated from HD and HF patients represented a mixed population that coexpresses both mesenchymal and myogenic markers and differs from AD-MMSC, BM-MMSC, and IMF-MSC. The functional properties of SM-MPC did not differ between HD and HF patients. Conclusion. In the present work, we demonstrate that the metabolic and functional alterations we detected in skeletal muscle from HF patients do not dramatically affect the functional properties of purified and expanded in vitro SM-MPC. We speculate that skeletal muscle progenitor cells are protected by their niche and under beneficial circumstances could contribute to muscle restoration and prevention and treatment of muscle wasting. The potential new therapeutic strategies of HF-induced skeletal muscle wasting should be targeted on both activation of SM-MPC regeneration potential and improvement of skeletal muscle metabolic status to provide a favorable environment for SM-MPC-driven muscle restoration.

The ubiquitin–proteasome system and skeletal muscle wasting

2005 ◽  
Vol 41 (1) ◽  
pp. 173 ◽  
Author(s):  
Didier Attaix ◽  
Sophie Ventadour ◽  
Audrey Codran ◽  
Daniel Béchet ◽  
Daniel Taillandier ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Wasting ◽  
Ubiquitin Proteasome System ◽  
Skeletal Muscle Wasting ◽  
Ubiquitin Proteasome

scholarly journals Mitochondrial Dysfunction Is a Common Denominator Linking Skeletal Muscle Wasting Due to Disease, Aging, and Prolonged Inactivity

Antioxidants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 588
Author(s):  
Hayden W. Hyatt ◽  
Scott K. Powers
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Dysfunction ◽  
Chronic Diseases ◽  
Muscle Mass ◽  
Cancer Chemotherapy ◽  
Muscle Wasting ◽  
The Body ◽  
Common Denominator ◽  
Skeletal Muscle Wasting ◽  
Vital Functions

Skeletal muscle is the most abundant tissue in the body and is required for numerous vital functions, including breathing and locomotion. Notably, deterioration of skeletal muscle mass is also highly correlated to mortality in patients suffering from chronic diseases (e.g., cancer). Numerous conditions can promote skeletal muscle wasting, including several chronic diseases, cancer chemotherapy, aging, and prolonged inactivity. Although the mechanisms responsible for this loss of muscle mass is multifactorial, mitochondrial dysfunction is predicted to be a major contributor to muscle wasting in various conditions. This systematic review will highlight the biochemical pathways that have been shown to link mitochondrial dysfunction to skeletal muscle wasting. Importantly, we will discuss the experimental evidence that connects mitochondrial dysfunction to muscle wasting in specific diseases (i.e., cancer and sepsis), aging, cancer chemotherapy, and prolonged muscle inactivity (e.g., limb immobilization). Finally, in hopes of stimulating future research, we conclude with a discussion of important future directions for research in the field of muscle wasting.

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