Myriocin prevents muscle ceramide accumulation but not muscle fiber atrophy during short-term mechanical unloading

2016 ◽  
Vol 120 (2) ◽  
pp. 178-187 ◽  
Author(s):  
Erwann Salaun ◽  
Luz Lefeuvre-Orfila ◽  
Thibault Cavey ◽  
Brice Martin ◽  
Bruno Turlin ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Muscle Weakness ◽  
Muscle Atrophy ◽  
De Novo ◽  
Fiber Diameter ◽  
Sphingolipid Metabolism ◽  
Skeletal Muscle Atrophy ◽  
De Novo Synthesis ◽  
Skeletal Muscle Weakness

Bedridden patients in intensive care unit or after surgery intervention commonly develop skeletal muscle weakness. The latter is promoted by a variety of prolonged hospitalization-associated conditions. Muscle disuse is the most ubiquitous and contributes to rapid skeletal muscle atrophy and progressive functional strength reduction. Disuse causes a reduction in fatty acid oxidation, leading to its accumulation in skeletal muscle. We hypothesized that muscle fatty acid accumulation could stimulate ceramide synthesis and promote skeletal muscle weakness. Therefore, the present study was designed to determine the effects of sphingolipid metabolism on skeletal muscle atrophy induced by 7 days of disuse. For this purpose, male Wistar rats were treated with myriocin, an inhibitor of de novo synthesis of ceramides, and subjected to hindlimb unloading (HU) for 7 days. Soleus muscles were assayed for fiber diameter, ceramide levels, protein degradation, and apoptosis signaling. Serum and liver were removed to evaluate the potential hepatoxicity of myriocin treatment. We found that HU increases content of saturated C16:0 and C18:0 ceramides and decreases soleus muscle weight and fiber diameter. HU increased the level of polyubiquitinated proteins and induced apoptosis in skeletal muscle. Despite a prevention of C16:0 and C18:0 muscle accumulation, myriocin treatment did not prevent skeletal muscle atrophy and concomitant induction of apoptosis and proteolysis. Moreover, myriocin treatment increased serum transaminases and induced hepatocyte necrosis. These data highlight that inhibition of de novo synthesis of ceramides during immobilization is not an efficient strategy to prevent skeletal muscle atrophy and exerts adverse effects like hepatotoxicity.

scholarly journals Sphingosine-1-phosphate analog FTY720 reverses obesity but not age-induced anabolic resistance to muscle contraction

2019 ◽  
Vol 317 (3) ◽  
pp. C502-C512
Author(s):  
Donato A. Rivas ◽  
Nicholas P. Rice ◽  
Yassine Ezzyat ◽  
Devin J. McDonald ◽  
Brittany E. Cooper ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Palmitic Acid ◽  
Muscle Contraction ◽  
Chronic Inflammation ◽  
Muscle Atrophy ◽  
Muscle Cells ◽  
Skeletal Muscle Atrophy ◽  
Anabolic Resistance ◽  
Sphingosine 1 Phosphate

Sarcopenia, the age-associated loss of skeletal muscle mass and function, is coupled with declines in physical functioning leading to subsequent higher rates of disability, frailty, morbidity, and mortality. Aging and obesity independently contribute to muscle atrophy that is assumed to be a result of the activation of mutual physiological pathways. Understanding mechanisms contributing to the induction of skeletal muscle atrophy with aging and obesity is important for determining targets that may have pivotal roles in muscle loss in these conditions. We find that aging and obesity equally induce an anabolic resistance to acute skeletal muscle contraction as observed with decreases in anabolic signaling activation after contraction. Furthermore, treatment with the sphingosine-1-phosphate analog FTY720 for 4 wk increased lean mass and strength, and the anabolic signaling response to contraction was improved in obese but not older animals. To determine the role of chronic inflammation and different fatty acids on anabolic resistance in skeletal muscle cells, we overexpressed IKKβ with and without exposure to saturated fatty acid (SFA; palmitic acid), polyunsaturated fatty acid (eicosapentaenoic acid), and monounsaturated fatty acid (oleic acid). We found that IKKβ overexpression increased inflammation markers in muscle cells, and this chronic inflammation exacerbated anabolic resistance in response to SFA. Pretreatment with FTY720 reversed the inflammatory effects of palmitic acid in the muscle cells. Taken together, these data demonstrate chronic inflammation can induce anabolic resistance, SFA aggravates these effects, and FTY720 can reverse this by decreasing ceramide accumulation in skeletal muscle.

scholarly journals Parkin Overexpression Attenuates Sepsis-Induced Muscle Wasting

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1454 ◽  
Author(s):  
Jean-Philippe Leduc-Gaudet ◽  
Dominique Mayaki ◽  
Olivier Reynaud ◽  
Felipe E. Broering ◽  
Tomer J. Chaffer ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Cecal Ligation ◽  
Body Weight Loss ◽  
Skeletal Muscle Atrophy ◽  
Transmission Electron ◽  
Mitochondrial Functions ◽  
Skeletal Muscle Weakness ◽  
Autophagy Pathway ◽  
Old Mice

Sepsis elicits skeletal muscle weakness and fiber atrophy. The accumulation of injured mitochondria and depressed mitochondrial functions are considered as important triggers of sepsis-induced muscle atrophy. It is unclear whether mitochondrial dysfunctions in septic muscles are due to the inadequate activation of quality control processes. We hypothesized that overexpressing Parkin, a protein responsible for the recycling of dysfunctional mitochondria by the autophagy pathway (mitophagy), would confer protection against sepsis-induced muscle atrophy by improving mitochondrial quality and content. Parkin was overexpressed for four weeks in the limb muscles of four-week old mice using intramuscular injections of adeno-associated viruses (AAVs). The cecal ligation and perforation (CLP) procedure was used to induce sepsis. Sham operated animals were used as controls. All animals were studied for 48 h post CLP. Sepsis resulted in major body weight loss and myofiber atrophy. Parkin overexpression prevented myofiber atrophy in CLP mice. Quantitative two-dimensional transmission electron microscopy revealed that sepsis is associated with the accumulation of enlarged and complex mitochondria, an effect which was attenuated by Parkin overexpression. Parkin overexpression also prevented a sepsis-induced decrease in the content of mitochondrial subunits of NADH dehydrogenase and cytochrome C oxidase. We conclude that Parkin overexpression prevents sepsis-induced skeletal muscle atrophy, likely by improving mitochondrial quality and contents.

scholarly journals Thyroid Hormone Protects from Fasting-Induced Skeletal Muscle Atrophy by Promoting Metabolic Adaptation

2019 ◽  
Vol 20 (22) ◽  
pp. 5754 ◽  
Author(s):  
Ucci ◽  
Renzini ◽  
Russi ◽  
Mangialardo ◽  
Cammarata ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Thyroid Hormone ◽  
Muscle Atrophy ◽  
De Novo ◽  
Skeletal Muscle Atrophy ◽  
Metabolic Adaptation ◽  
Cell Proliferation And Differentiation ◽  
Wide Range ◽  
Ubiquitin Proteasome ◽  
Muscle Homeostasis

Thyroid hormones regulate a wide range of cellular responses, via non-genomic and genomic actions, depending on cell-specific thyroid hormone transporters, co-repressors, or co-activators. Skeletal muscle has been identified as a direct target of thyroid hormone T3, where it regulates stem cell proliferation and differentiation, as well as myofiber metabolism. However, the effects of T3 in muscle-wasting conditions have not been yet addressed. Being T3 primarily responsible for the regulation of metabolism, we challenged mice with fasting and found that T3 counteracted starvation-induced muscle atrophy. Interestingly, T3 did not prevent the activation of the main catabolic pathways, i.e., the ubiquitin-proteasome or the autophagy-lysosomal systems, nor did it stimulate de novo muscle synthesis in starved muscles. Transcriptome analyses revealed that T3 mainly affected the metabolic processes in starved muscle. Further analyses of myofiber metabolism revealed that T3 prevented the starvation-mediated metabolic shift, thus preserving skeletal muscle mass. Our study elucidated new T3 functions in regulating skeletal muscle homeostasis and metabolism in pathological conditions, opening to new potential therapeutic approaches for the treatment of skeletal muscle atrophy.

scholarly journals Relation between skeletal muscle strength and ubiquitin ligase expression in muscle atrophy models in zebrafish larvae (Danio Rerio)

2020 ◽  
Author(s):  
Jiao Liu ◽  
Elisabeth Le ◽  
Matthias Schwartzkopf ◽  
Anders Arner
Keyword(s):  
Skeletal Muscle ◽  
Food Intake ◽  
Muscle Weakness ◽  
Muscle Atrophy ◽  
Ubiquitin Ligase ◽  
Muscle Function ◽  
Skeletal Muscle Atrophy ◽  
Active Force ◽  
Zebrafish Larvae

Abstract Background Skeletal muscle atrophy is often seen in patients with chronic diseases or muscle disuse. Upregulated expression of ubiquitin ligases such as Muscle Ring Finger 1 (MuRF-1) and Muscle Atrophy F-box (MAFbx) has been shown in different immobilization-induced atrophy models, which is believed to be responsible for the enhanced muscle protein proteolysis and thereafter results in muscle weakness. However, currently used immobilization animal models can include artefacts due to difficulty of food intake and stress. Zebrafish larvae 5-6 days after hatching do not require active movement for food intake, and it is possible to assess the muscle function of their trunk muscle. Therefore, we established two muscle atrophy models using zebrafish larvae and aimed to investigate the role of the MuRFs and MAFbx in relation with muscle function.Methods An actin-myosin interaction blocker (BTS) was used to immobilize zebrafish larvae from 3-6 days after hatching; in another series, dexamethasone was fed to larvae from 3-5 days after hatching. Maximal active force of trunk muscles was examined and the distance between adjacent filaments in sarcomeric structure was measured using small angle x-ray diffraction. MuRF and MAFbx expression was determined using real time PCR. Two-way ANOVA was used to analyze the difference between groups.Results We found a significant up-regulation of MuRF-1 and a lower active force generation in dexamethasone treated larvae. However, although the BTS immobilization induced muscle weakness, it was associated with decreased of MuRF-1 to 3 and MAFbx. After 3 days of immobilization, sarcomere became more compressed compared to the controls.Conclusions Two kinds of muscle atrophy models were successfully established in zebrafish larvae. MuRFs and MAFbx was lowered in BTS treated model whereas MuRF-1 was up-regulated in dexamethasone treated model implicating the complex role of ubiquitin ligase in different muscle atrophy models.

P5.65 The effects of Omega-3 fatty acid on skeletal muscle atrophy induced by Dexamethasone

2011 ◽  
Vol 21 (9-10) ◽  
pp. 744
Author(s):  
A. Fappi ◽  
T.S. Godoy ◽  
D.P. Venâncio ◽  
G. Chadi ◽  
E. Zanoteli
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Muscle Atrophy ◽  
Skeletal Muscle Atrophy ◽  
Omega 3 ◽  
Omega 3 Fatty Acid

scholarly journals TNFalpha- and tumor-induced skeletal muscle atrophy involves sphingolipid metabolism

2012 ◽  
Vol 2 (1) ◽  
pp. 2 ◽  
Author(s):  
Joffrey De Larichaudy ◽  
Alessandra Zufferli ◽  
Filippo Serra ◽  
Andrea M Isidori ◽  
Fabio Naro ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Sphingolipid Metabolism ◽  
Skeletal Muscle Atrophy

scholarly journals Vitamin K2 as a New Modulator of the Ceramide De Novo Synthesis Pathway

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3377
Author(s):  
Adrian Kołakowski ◽  
Piotr F. Kurzyna ◽  
Hubert Żywno ◽  
Wiktor Bzdęga ◽  
Ewa Harasim-Symbor ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Insulin Signaling ◽  
High Performance ◽  
De Novo ◽  
Vitamin K2 ◽  
Sphingolipid Metabolism ◽  
Fatty Acid Transport ◽  
Acid Uptake ◽  
De Novo Synthesis ◽  
Expression Ratio

The aim of the study was to evaluate the influence of vitamin K2 (VK2) supplementation on the sphingolipid metabolism pathway in palmitate-induced insulin resistant hepatocytes. The study was carried out on human hepatocellular carcinoma cells (HepG2) incubated with VK2 and/or palmitic acid (PA). The concentrations of sphingolipids were measured by high-performance liquid chromatography. The expression of enzymes from the sphingolipid pathway was assessed by Western blotting. The same technique was used in order to determine changes in the expression of the proteins from the insulin signaling pathway in the cells. Simultaneous incubation of HepG2 cells with palmitate and VK2 elevated accumulation of sphinganine and ceramide with increased expression of enzymes from the ceramide de novo synthesis pathway. HepG2 treatment with palmitate and VK2 significantly decreased the insulin-stimulated expression ratio of insulin signaling proteins. Moreover, we observed that the presence of PA w VK2 increased fatty acid transport protein 2 expression. Our study showed that VK2 activated the ceramide de novo synthesis pathway, which was confirmed by the increase in enzymes expression. VK2 also intensified fatty acid uptake, ensuring substrates for sphingolipid synthesis through the de novo pathway. Furthermore, increased concentration of sphingolipids, mainly sphinganine, inhibited insulin pathway proteins phosphorylation, increasing insulin resistance development.

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