scholarly journals Fibroblast growth factor 23 does not directly influence skeletal muscle cell proliferation and differentiation or ex vivo muscle contractility

2018 ◽  
Vol 315 (4) ◽  
pp. E594-E604 ◽  
Author(s):  
Keith G. Avin ◽  
Julian A. Vallejo ◽  
Neal X. Chen ◽  
Kun Wang ◽  
Chad D. Touchberry ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Skeletal Muscle ◽  
Chronic Kidney Disease ◽  
Ex Vivo ◽  
Fibroblast Growth Factor 23 ◽  
Hypophosphatemic Rickets ◽  
Muscle Dysfunction ◽  
Fibroblast Growth ◽  
Muscle Contractility ◽  
Skeletal Muscle Dysfunction

Skeletal muscle dysfunction accompanies the clinical disorders of chronic kidney disease (CKD) and hereditary hypophosphatemic rickets. In both disorders, fibroblast growth factor 23 (FGF23), a bone-derived hormone regulating phosphate and vitamin D metabolism, becomes chronically elevated. FGF23 has been shown to play a direct role in cardiac muscle dysfunction; however, it is unknown whether FGF23 signaling can also directly induce skeletal muscle dysfunction. We found expression of potential FGF23 receptors ( Fgfr1–4) and α-Klotho in muscles of two animal models (CD-1 and Cy/+ rat, a naturally occurring rat model of chronic kidney disease-mineral bone disorder) as well as C2C12 myoblasts and myotubes. C2C12 proliferation, myogenic gene expression, oxidative stress marker 8-OHdG, intracellular Ca2+ ([Ca2+]i), and ex vivo contractility of extensor digitorum longus (EDL) or soleus muscles were assessed after treatment with various amounts of FGF23. FGF23 (2–100 ng/ml) did not alter C2C12 proliferation, expression of myogenic genes, or oxidative stress after 24- to 72-h treatment. Acute or prolonged FGF23 treatment up to 6 days did not alter C2C12 [Ca2+]i handling, nor did acute treatment with FGF23 (9–100 ng/ml) affect EDL and soleus muscle contractility. In conclusion, although skeletal muscles express the receptors involved in FGF23-mediated signaling, in vitro FGF23 treatments failed to directly alter skeletal muscle development or function under the conditions tested. We hypothesize that other endogenous substances may be required to act in concert with FGF23 or apart from FGF23 to promote muscle dysfunction in hereditary hypophosphatemic rickets and CKD.

scholarly journals Sarcopenia in chronic kidney disease – A brief review

2021 ◽  
Vol 35 (2) ◽  
Author(s):  
Beatriz Donato ◽  
◽  
Catarina Teixeira ◽  
Sónia Velho ◽  
Edgar Almeida ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Muscle Mass ◽  
Physical Performance ◽  
Functional Independence ◽  
Muscle Dysfunction ◽  
Skeletal Muscle Dysfunction ◽  
Age Related ◽  
The Impact

Sarcopenia is a progressive age -related loss of muscle mass associated with a decline in muscle function and physical performance. Patients with chronic kidney disease experience substantial loss of muscle mass, weakness, and poor physical performance. Indeed, with the progression of chronic kidney disease, skeletal muscle dysfunction contributes to mobility limitation, loss of functional independence, and vulnerability to disease complications. There is a lack of robust data on the negative effect of the impact of kidney disease on skeletal muscle dysfunction, as well as on screening and treatment strategies that can be used in clinical practice to prevent functional decline and disability. Therefore, sarcopenia may be an underestimated condition with major implications for people with chronic kidney disease, even before the start of dialysis, which makes research into this topic necessary. The purpose of this review is to expand on some fundamental topics of sarcopenia, with an emphasis on the setting of chronic kidney disease patients.

scholarly journals FGF23 impairs peripheral microvascular function in renal failure

2018 ◽  
Vol 315 (5) ◽  
pp. H1414-H1424 ◽  
Author(s):  
Melissa Verkaik ◽  
Rio P. Juni ◽  
Ellen P. M. van Loon ◽  
Erik M. van Poelgeest ◽  
Rick F. J. Kwekkeboom ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Endothelial Dysfunction ◽  
Kidney Disease ◽  
Asymmetric Dimethylarginine ◽  
Ex Vivo ◽  
Fibroblast Growth Factor 23 ◽  
Fibroblast Growth

Cardiovascular diseases account for ~50% of mortality in patients with chronic kidney disease (CKD). Fibroblast growth factor 23 (FGF23) is independently associated with endothelial dysfunction and cardiovascular mortality. We hypothesized that CKD impairs microvascular endothelial function and that this can be attributed to FGF23. Mice were subjected to partial nephrectomy (5/6Nx) or sham surgery. To evaluate the functional role of FGF23, non-CKD mice received FGF23 injections and CKD mice received FGF23-blocking antibodies after 5/6Nx surgery. To examine microvascular function, myocardial perfusion in vivo and vascular function of gracilis resistance arteries ex vivo were assessed in mice. 5/6Nx surgery blunted ex vivo vasodilator responses to acetylcholine, whereas responses to sodium nitroprusside or endothelin were normal. In vivo FGF23 injections in non-CKD mice mimicked this endothelial defect, and FGF23 antibodies in 5/6Nx mice prevented endothelial dysfunction. Stimulation of microvascular endothelial cells with FGF23 in vitro did not induce ERK phosphorylation. Increased plasma asymmetric dimethylarginine concentrations were increased by FGF23 and strongly correlated with endothelial dysfunction. Increased FGF23 concentration did not mimic impaired endothelial function in the myocardium of 5/6Nx mice. In conclusion, impaired peripheral endothelium-dependent vasodilatation in 5/6Nx mice is mediated by FGF23 and can be prevented by blocking FGF23. These data corroborate FGF23 as an important target to combat cardiovascular disease in CKD.NEW & NOTEWORTHY In the present study, we provide the first evidence that fibroblast growth factor 23 (FGF23) is a cause of peripheral endothelial dysfunction in a model of early chronic kidney disease (CKD) and that endothelial dysfunction in CKD can be prevented by blockade of FGF23. This pathological effect on endothelial cells was induced by long-term exposure of physiological levels of FGF23. Mechanistically, increased plasma asymmetric dimethylarginine concentrations were strongly associated with this endothelial dysfunction in CKD and were increased by FGF23.

scholarly journals Ascorbate infusion increases skeletal muscle fatigue resistance in patients with chronic obstructive pulmonary disease

2013 ◽  
Vol 305 (10) ◽  
pp. R1163-R1170 ◽  
Author(s):  
Matthew J. Rossman ◽  
Ryan S. Garten ◽  
H. Jonathan Groot ◽  
Van Reese ◽  
Jia Zhao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Chronic Obstructive Pulmonary Disease ◽  
Skeletal Muscle ◽  
Antioxidant Capacity ◽  
Chronic Obstructive ◽  
Muscle Dysfunction ◽  
Obstructive Pulmonary Disease ◽  
Skeletal Muscle Fatigue ◽  
Systemic Oxidative Stress ◽  
Skeletal Muscle Dysfunction

Chronic obstructive pulmonary disease (COPD) is associated with systemic oxidative stress and skeletal muscle dysfunction. The purpose of this study was to examine the impact of intravenous ascorbate administration (AO) on biological markers of antioxidant capacity and oxidative stress, and subsequently skeletal muscle function during dynamic, small muscle mass exercise in patients with COPD. Ten patients with spirometric evidence of COPD performed single-leg knee extensor (KE) trials matched for intensity and time (isotime) following intravenous ascorbate (2 g) or saline infusion (PL). Quadriceps fatigue was quantified by changes in force elicited by maximal voluntary contraction (MVC) and magnetic femoral nerve stimulation (Qtw,pot). AO administration significantly increased antioxidant capacity, as measured by the ferric-reducing ability of plasma (PL: 1 ± 0.1 vs. AO: 5 ± 0.2 mM), and significantly reduced malondialdehyde levels (PL: 1.16 ± 0.1 vs. AO: 0.97 ± 0.1 mmol). Additionally, resting blood pressure was significantly reduced (PL: 104 ± 4 vs. AO: 93 ± 6 mmHg) and resting femoral vascular conductance was significantly elevated after AO (PL: 2.4 ± 0.2 vs. AO: 3.6 ± 0.4 ml·min−1·mmHg−1). During isotime exercise, the AO significantly attenuated both the ventilatory and metabolic responses, and patients accumulated significantly less peripheral quadriceps fatigue, as illustrated by less of a fall in MVC (PL: −11 ± 2% vs. AO: −5 ± 1%) and Qtw,pot (PL: −37 ± 1% vs. AO: −30 ± 2%). These data demonstrate a beneficial role of AO administration on skeletal muscle fatigue in patients with COPD and further implicate systemic oxidative stress as a causative factor in the skeletal muscle dysfunction observed in this population.

scholarly journals Prevention of Doxorubicin-Induced Autophagy Attenuates Oxidative Stress and Skeletal Muscle Dysfunction

Antioxidants ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 263 ◽  
Author(s):  
Vivian Doerr ◽  
Ryan N. Montalvo ◽  
Oh Sung Kwon ◽  
Erin E. Talbert ◽  
Brian A. Hain ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Dominant Negative ◽  
Skeletal Muscle Atrophy ◽  
Muscle Dysfunction ◽  
Related Factor ◽  
Skeletal Muscle Dysfunction ◽  
Dominant Negative Mutation

Clinical use of the chemotherapeutic doxorubicin (DOX) promotes skeletal muscle atrophy and weakness, adversely affecting patient mobility and strength. Although the mechanisms responsible for DOX-induced skeletal muscle dysfunction remain unclear, studies implicate the significant production of reactive oxygen species (ROS) in this pathology. Supraphysiological ROS levels can enhance protein degradation via autophagy, and it is established that DOX upregulates autophagic signaling in skeletal muscle. To determine the precise contribution of accelerated autophagy to DOX-induced skeletal muscle dysfunction, we inhibited autophagy in the soleus via transduction of a dominant negative mutation of the autophagy related 5 (ATG5) protein. Targeted inhibition of autophagy prevented soleus muscle atrophy and contractile dysfunction acutely following DOX administration, which was associated with a reduction in mitochondrial ROS and maintenance of mitochondrial respiratory capacity. These beneficial modifications were potentially the result of enhanced transcription of antioxidant response element-related genes and increased antioxidant capacity. Specifically, our results showed significant upregulation of peroxisome proliferator-activated receptor gamma co-activator 1-alpha, nuclear respiratory factor-1, nuclear factor erythroid-2-related factor-2, nicotinamide-adenine dinucleotide phosphate quinone dehydrogenase-1, and catalase in the soleus with DOX treatment when autophagy was inhibited. These findings establish a significant role of autophagy in the development of oxidative stress and skeletal muscle weakness following DOX administration.

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