scholarly journals Acute Succinate Administration Increases Oxidative Phosphorylation and Skeletal Muscle Explosive Strength via SUCNR1

2022 ◽  
Vol 8 ◽  
Author(s):  
Guli Xu ◽  
Yexian Yuan ◽  
Pei Luo ◽  
Jinping Yang ◽  
Jingjing Zhou ◽  
...  

Endurance training and explosive strength training, with different contraction protein and energy metabolism adaptation in skeletal muscle, are both beneficial for physical function and quality of life. Our previous study found that chronic succinate feeding enhanced the endurance exercise of mice by inducing skeletal muscle fiber-type transformation. The purpose of this study is to investigate the effect of acute succinate administration on skeletal muscle explosive strength and its potential mechanism. Succinate was injected to mature mice to explore the acute effect of succinate on skeletal muscle explosive strength. And C2C12 cells were used to verify the short-term effect of succinate on oxidative phosphorylation. Then the cells interfered with succinate receptor 1 (SUCNR1) siRNA, and the SUCNR1-GKO mouse model was used for verifying the role of SUCNR1 in succinate-induced muscle metabolism and expression and explosive strength. The results showed that acute injection of succinate remarkably improved the explosive strength in mice and also decreased the ratio of nicotinamide adenine dinucleotide (NADH) to NAD+ and increased the mitochondrial complex enzyme activity and creatine kinase (CK) activity in skeletal muscle tissue. Similarly, treatment of C2C12 cells with succinate revealed that succinate significantly enhanced oxidative phosphorylation with increased adenosine triphosphate (ATP) content, CK, and the activities of mitochondrial complex I and complex II, but with decreased lactate content, reactive oxygen species (ROS) content, and NADH/NAD+ ratio. Moreover, the succinate's effects on oxidative phosphorylation were blocked in SUCNR1-KD cells and SUCNR1-KO mice. In addition, succinate-induced explosive strength was also abolished by SUCNR1 knockout. All the results indicate that acute succinate administration increases oxidative phosphorylation and skeletal muscle explosive strength in a SUCNR1-dependent manner.

2013 ◽  
Vol 115 (10) ◽  
pp. 1457-1463 ◽  
Author(s):  
Tara L. MacDonald ◽  
Zhongxiao Wan ◽  
Scott Frendo-Cumbo ◽  
David J. Dyck ◽  
David C. Wright

IL-6 is an exercise-regulated myokine that has been suggested to increase lipolysis in fast-twitch skeletal muscle. However, it is not known if a similar effect is present in slow-twitch muscle. Furthermore, epinephrine increases IL-6 secretion from skeletal muscle, suggesting that IL-6 could play a role in mediating the lipolytic effects of catecholamines. The purpose of this study was to determine whether IL-6 stimulates skeletal muscle lipolysis in a fiber type dependent manner and is required for epinephrine-stimulated lipolysis in murine skeletal muscle. Soleus and extensor digitorum longus (EDL) muscles from male C57BL/6J wild-type and IL-6−/− mice were incubated with 1 μM (183 ng/ml) epinephrine or 75 ng/ml recombinant IL-6 (rIL-6) for 60 min. IL-6 treatment increased 5′-AMP-activated protein kinase and signal transducer and activator of transcription 3 phosphorylation and glycerol release in isolated EDL but not soleus muscles from C57BL/6J mice. Conversely, epinephrine increased glycerol release in soleus but not EDL muscles from C57BL/6J mice. Basal lipolysis was elevated in soleus muscle from IL-6−/− mice, and this was associated with increases in adipose triglyceride lipase (ATGL) and its coactivator comparative gene identification-58 (CGI-58). The increase in ATGL content does not appear to be due to a loss of IL-6's direct effects, because ex vivo treatment with IL-6 failed to alter the expression of ATGL mRNA in soleus muscle. In summary, IL-6 stimulates lipolysis in glycolytic but not oxidative muscle, whereas the opposite fiber type effect is seen with epinephrine. The absence of IL-6 indirectly upregulates lipolysis, and this is associated with increases in ATGL and its coactivator CGI-58.


2017 ◽  
Vol 110 ◽  
pp. 381-389 ◽  
Author(s):  
Ricardo A. Pinho ◽  
Diane M. Sepa-Kishi ◽  
George Bikopoulos ◽  
Michelle V. Wu ◽  
Abinas Uthayakumar ◽  
...  

2014 ◽  
Vol 53 (3) ◽  
pp. 331-343 ◽  
Author(s):  
Ana P Irazoqui ◽  
Ricardo L Boland ◽  
Claudia G Buitrago

Previously, we have reported that 1,25(OH)2-vitamin D3(1,25D) activates p38 MAPK (p38) in a vitamin D receptor (VDR)-dependent manner in proliferative C2C12 myoblast cells. It was also demonstrated that 1,25D promotes muscle cell proliferation and differentiation. However, we did not study these hormone actions in depth. In this study we have investigated whether the VDR and p38 participate in the signaling mechanism triggered by 1,25D. In C2C12 cells, the VDR was knocked down by a shRNA, and p38 was specifically inhibited using SB-203580. Results from cell cycle studies indicated that hormone stimulation prompts a peak of S-phase followed by an arrest in the G0/G1-phase, events which were dependent on VDR and p38. Moreover, 1,25D increases the expression of cyclin D3 and the cyclin-dependent kinase inhibitors, p21Waf1/Cip1and p27Kip1, while cyclin D1 protein levels did not change during G0/G1 arrest. In all these events, p38 and VDR were required. At the same time, a 1,25D-dependent acute increase in myogenin expression was observed, indicating that the G0/G1 arrest of cells is a pro-differentiative event. Immunocytochemical assays revealed co-localization of VDR and cyclin D3, promoted by 1,25D in a p38-dependent manner. When cyclin D3 expression was silenced, VDR and myogenin levels were downregulated, indicating that cyclin D3 was required for 1,25D-induced VDR expression and the concomitant entrance into the differentiation process. In conclusion, the VDR and p38 are involved in control of the cellular cycle by 1,25D in skeletal muscle cells, providing key information on the mechanisms underlying hormone regulation of myogenesis.


2006 ◽  
Vol 290 (1) ◽  
pp. R233-R240 ◽  
Author(s):  
Bankim A. Bhatt ◽  
John J. Dube ◽  
Nikolas Dedousis ◽  
Jodie A. Reider ◽  
Robert M. O’Doherty

Increased activity of proinflammatory/stress pathways has been implicated in the pathogenesis of insulin resistance in obesity. However, the effects of obesity on the activity of these pathways in skeletal muscle, the major insulin-sensitive tissue by mass, are poorly understood. Furthermore, the mechanisms that activate proinflammatory/stress pathways in obesity are unknown. The present study addressed the effects of diet-induced obesity (DIO; 6 wk of high-fat feeding) and acute (6-h) hyperlipidemia (HL) in rats on activity of IKK/IκB/NF-κB c-Jun NH2-terminal kinase, and p38 MAPK in three skeletal muscles differing in fiber type [superficial vastus (Vas; fast twitch-glycolytic), soleus (Sol; slow twitch-oxidative), and gastrocnemius (Gas; mixed)]. DIO decreased the levels of the IκBα in Vas (24 ± 3%, P = 0.001, n = 8) but not in Sol or Gas compared with standard chow-fed controls. Similar to DIO, HL decreased IκBα levels in Vas (26 ± 5%, P = 0.006, n = 6) and in Gas (15 ± 4%, P = 0.01, n = 7) but not in Sol compared with saline-infused controls. Importantly, the fiber-type-dependent effects on IκBα levels could not be explained by differential accumulation of triglyceride in Sol and Vas. HL, but not DIO, decreased phospho-p38 MAPK levels in Vas (41 ± 7% P = 0.004, n = 6) but not in Sol or Gas. Finally, skeletal muscle c-Jun NH2-terminal kinase activity was unchanged by DIO or HL. We conclude that diet-induced obesity and acute HL reduce IκBα levels in rat skeletal muscle in a fiber-type-dependent manner.


2021 ◽  
Vol 35 (S1) ◽  
Author(s):  
Chris Kargl ◽  
Autumn Yang ◽  
Zhihao Jia ◽  
Shihuan Kuang ◽  
Jonathan Shannahan ◽  
...  

2008 ◽  
Vol 183 (6) ◽  
pp. 1033-1048 ◽  
Author(s):  
Belinda S. Cowling ◽  
Meagan J. McGrath ◽  
Mai-Anh Nguyen ◽  
Denny L. Cottle ◽  
Anthony J. Kee ◽  
...  

Regulators of skeletal muscle mass are of interest, given the morbidity and mortality of muscle atrophy and myopathy. Four-and-a-half LIM protein 1 (FHL1) is mutated in several human myopathies, including reducing-body myopathy (RBM). The normal function of FHL1 in muscle and how it causes myopathy remains unknown. We find that FHL1 transgenic expression in mouse skeletal muscle promotes hypertrophy and an oxidative fiber-type switch, leading to increased whole-body strength and fatigue resistance. Additionally, FHL1 overexpression enhances myoblast fusion, resulting in hypertrophic myotubes in C2C12 cells, (a phenotype rescued by calcineurin inhibition). In FHL1-RBM C2C12 cells, there are no hypertrophic myotubes. FHL1 binds with the calcineurin-regulated transcription factor NFATc1 (nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1), enhancing NFATc1 transcriptional activity. Mutant RBM-FHL1 forms aggregate bodies in C2C12 cells, sequestering NFATc1 and resulting in reduced NFAT nuclear translocation and transcriptional activity. NFATc1 also colocalizes with mutant FHL1 to reducing bodies in RBM-afflicted skeletal muscle. Therefore, via NFATc1 signaling regulation, FHL1 appears to modulate muscle mass and strength enhancement.


2010 ◽  
Vol 299 (6) ◽  
pp. C1549-C1561 ◽  
Author(s):  
Lindsey D. Bogachus ◽  
Lorraine P. Turcotte

Metformin is known to improve insulin sensitivity in part via a rise in AMP-activated protein kinase (AMPK) activity and alterations in muscle metabolism. However, a full understanding of how metformin alters AMPK-α1 vs. AMPK-α2 activation remains unknown. To study this question, L6 skeletal muscle cells were treated with or without RNAi oligonucleotide sequences to downregulate AMPK-α1 or AMPK-α2 protein expression and incubated with or without 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) or metformin and/or insulin. In contrast to AICAR, which preferentially activated AMPK-α2, metformin preferentially activated AMPK-α1 in a dose- and time-dependent manner. Metformin increased ( P < 0.05) glucose uptake and plasma membrane (PM) Glut4 in a dose- and time-dependent manner. Metformin significantly reduced palmitate uptake ( P < 0.05) and oxidation ( P < 0.05), and this was accompanied by a similar decrease ( P < 0.05) in PM CD36 content but with no change in acetyl-CoA carboxylase (ACC) phosphorylation ( P > 0.05). AICAR and metformin similarly increased ( P < 0.05) nuclear silent mating-type information regulator 2 homolog 1 (SIRT1) activity. Downregulation of AMPK-α1 completely prevented the metformin-induced reduction in palmitate uptake and oxidation but only partially reduced the metformin-induced increase in glucose uptake. Downregulation of AMPK-α2 had no effect on metformin-induced glucose uptake, palmitate uptake, and oxidation. The increase in SIRT1 activity induced by metformin was not affected by downregulation of either AMPK-α1 or AMPK-α2. Our data indicate that, in muscle cells, the inhibitory effects of metformin on fatty acid metabolism occur via preferential phosphorylation of AMPK-α1, and the data indicate that cross talk between AMPK and SIRT1 does not favor either AMPK isozyme.


2014 ◽  
Vol 307 (4) ◽  
pp. R444-R454 ◽  
Author(s):  
Etienne Mouisel ◽  
Karima Relizani ◽  
Laurence Mille-Hamard ◽  
Raphaël Denis ◽  
Christophe Hourdé ◽  
...  

Myostatin (Mstn) participates in the regulation of skeletal muscle size and has emerged as a regulator of muscle metabolism. Here, we hypothesized that lack of myostatin profoundly depresses oxidative phosphorylation-dependent muscle function. Toward this end, we explored Mstn −/− mice as a model for the constitutive absence of myostatin and AAV-mediated overexpression of myostatin propeptide as a model of myostatin blockade in adult wild-type mice. We show that muscles from Mstn −/− mice, although larger and stronger, fatigue extremely rapidly. Myostatin deficiency shifts muscle from aerobic toward anaerobic energy metabolism, as evidenced by decreased mitochondrial respiration, reduced expression of PPAR transcriptional regulators, increased enolase activity, and exercise-induced lactic acidosis. As a consequence, constitutively reduced myostatin signaling diminishes exercise capacity, while the hypermuscular state of Mstn−/− mice increases oxygen consumption and the energy cost of running. We wondered whether these results are the mere consequence of the congenital fiber-type switch toward a glycolytic phenotype of constitutive Mstn −/− mice. Hence, we overexpressed myostatin propeptide in adult mice, which did not affect fiber-type distribution, while nonetheless causing increased muscle fatigability, diminished exercise capacity, and decreased Pparb/d and Pgc1a expression. In conclusion, our results suggest that myostatin endows skeletal muscle with high oxidative capacity and low fatigability, thus regulating the delicate balance between muscle mass, muscle force, energy metabolism, and endurance capacity.


Nutrients ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3089
Author(s):  
Tomohiko Shirakawa ◽  
Aki Miyawaki ◽  
Takuma Matsubara ◽  
Nobuaki Okumura ◽  
Hideto Okamoto ◽  
...  

Honeybees produce royal jelly (RJ) from their cephalic glands. Royal jelly is a source of nutrition for the queen honey bee throughout its lifespan and is also involved in fertility and longevity. Royal jelly has long been considered beneficial to human health. We recently observed that RJ delayed impairment of motor function during aging, affecting muscle fiber size. However, how RJ affects skeletal muscle metabolism and the functional component of RJ is as of yet unidentified. We demonstrate that feeding mice with RJ daily prevents a decrease in myofiber size following denervation without affecting total muscle weight. RJ did not affect atrophy-related genes but stimulated the expression of myogenesis-related genes, including IGF-1 and IGF receptor. Trans-10-hydroxy-2-decenoic acid (10H2DA) and 10-hydroxydecanoic acid (10HDAA), two major fatty acids contained in RJ. After ingestion, 10H2DA and 10HDAA are metabolized into 2-decenedioic acid (2DA) and sebacic acid (SA) respectively. We found that 10H2DA, 10HDAA, 2DA, and SA all regulated myogenesis of C2C12 cells, murine myoblast cells. These novel findings may be useful for potential preventative and therapeutic applications for muscle atrophy disease included in Sarcopenia, an age-related decline in skeletal muscle mass and strength.


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