scholarly journals Systemic IL-6 regulation of eccentric contraction-induced muscle protein synthesis

2018 ◽  
Vol 315 (1) ◽  
pp. C91-C103 ◽  
Author(s):  
Justin P. Hardee ◽  
Dennis K. Fix ◽  
Xuewen Wang ◽  
Edie C. Goldsmith ◽  
Ho-Jin Koh ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Muscle Protein ◽  
Contractile Activity ◽  
Muscle Protein Synthesis ◽  
Tibialis Anterior Muscle ◽  
Eccentric Contraction ◽  
Tumor Bearing ◽  
Gp130 Receptor ◽  
Mtorc1 Signaling ◽  
Mtorc1 Activation

Systemic cytokines and contractile activity are established regulators of muscle protein turnover. Paradoxically, the IL-6 cytokine family, which shares the ubiquitously expressed membrane gp130 receptor, has been implicated in skeletal muscle’s response to both contractions and cancer-induced wasting. Although we have reported that tumor-derived cachectic factors could suppress stretch-induced protein synthesis in cultured myotubes, the ability of systemic cytokines to disrupt in vivo eccentric contraction-induced protein synthesis has not been established. Therefore, we examined whether systemic IL-6 regulates basal and eccentric contraction-induced protein synthesis through muscle gp130 signaling. Systemic IL-6 overexpression was performed for 2 wk, and we then examined basal and eccentric contraction-induced protein synthesis and mammalian target of rapamycin complex 1 (mTORC1) signaling in tibialis anterior muscle of male wild-type, muscle-specific gp130 receptor knockout, and tumor-bearing ApcMin/+ mice. Systemic IL-6 overexpression suppressed basal protein synthesis and mTORC1 signaling independently of IL-6 level, which was rescued by muscle gp130 loss. Interestingly, only high systemic IL-6 levels suppressed eccentric contraction-induced protein synthesis. Systemic IL-6 overexpression in precachectic tumor-bearing ApcMin/+ mice accelerated cachexia development, which coincided with suppressed basal and eccentric contraction-induced muscle protein synthesis. The suppression of eccentric contraction-induced protein synthesis by IL-6 occurred independently of mTORC1 activation. Collectively, these findings demonstrate that basal protein synthesis suppression was more sensitive to circulating IL-6 compared with the induction of protein synthesis by eccentric contraction. However, systemic IL-6 can interact with the cancer environment to suppress eccentric contraction-induced protein synthesis independently of mTORC1 activation.

scholarly journals c-Myc overexpression increases ribosome biogenesis and protein synthesis independent of mTORC1 activation in mouse skeletal muscle

2021 ◽  
Author(s):  
Takahiro Mori ◽  
Satoru Ato ◽  
Jonas R. Knudsen ◽  
Carlos Henriquez-Olguin ◽  
Zhencheng Li ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Skeletal Muscles ◽  
Ribosome Biogenesis ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Mrna Translation ◽  
Adeno Associated Virus ◽  
Mtorc1 Signaling ◽  
Mtorc1 Activation

High-intensity muscle contractions (HiMC) are known to increase c-Myc expression which is known to stimulate ribosome biogenesis and protein synthesis in most cells. However, while c-Myc mRNA transcription and c-Myc mRNA translation have been shown to be upregulated following resistance exercise concomitantly with increased ribosome biogenesis, this has not been tested directly. We investigated the effect of adeno-associated virus (AAV)-mediated c-Myc overexpression, with or without fasting or percutaneous electrical stimulation-induced HiMC, on ribosome biogenesis and protein synthesis in adult mouse skeletal muscles. AAV-mediated overexpression of c-Myc in mouse skeletal muscles for 2 weeks increased the DNA polymerase subunit POL1 mRNA, 45S-pre-rRNA, total RNA, and muscle protein synthesis without altering mechanistic target of rapamycin complex 1 (mTORC1) signaling under both ad libitum and fasted conditions. RNA-seq analyses revealed that c-Myc overexpression mainly regulated ribosome biogenesis-related biological processes. The protein synthesis response to c-Myc overexpression mirrored the response with HiMC. No additional effect of combining c-Myc overexpression and HiMC was observed. Our results suggest that c-Myc overexpression is sufficient to stimulate skeletal muscle ribosome biogenesis and protein synthesis without activation of mTORC1. Therefore, the HiMC-induced increase in c-Myc may contribute to ribosome biogenesis and increased protein synthesis following HiMC.

scholarly journals C-Myc Overexpression Increases Ribosome Biogenesis and Protein Synthesis Independent of mTORC1 Activation in Mouse Skeletal Muscle

2020 ◽  
Author(s):  
Takahiro Mori ◽  
Satoru Ato ◽  
Jonas R. Knudsen ◽  
Carlos Henriquez-Olguin ◽  
Zhencheng Li ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Skeletal Muscles ◽  
Ribosome Biogenesis ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Rna Seq ◽  
Adeno Associated Virus ◽  
Mtorc1 Signaling ◽  
Mtorc1 Activation

Abstract Background: High-intensity muscle contractions (HiMC) are known to increase c-Myc expression which is known to stimulate ribosome biogenesis and protein synthesis in tumor cells. However, whether the increase in c-Myc stimulates ribosome biogenesis and protein synthesis in skeletal muscles remains unknown. Methods: We investigated the effect of adeno-associated virus (AAV)-mediated c-Myc overexpression, with or without fasting or percutaneous electrical stimulation-induced HiMC, on ribosome biogenesis and protein synthesis in adult mouse skeletal muscles. Results: AAV-mediated overexpression of c-Myc in mouse skeletal muscles for 2 weeks increased the DNA polymerase subunit POL1 mRNA, 45S-pre-rRNA, total RNA, and muscle protein synthesis without altering mechanistic target of rapamycin complex 1 (mTORC1) signaling under both ad libitum and fasted conditions. RNA-seq analyses revealed that c-Myc overexpression mainly regulated ribosome biogenesis-related biological processes. The protein synthesis response to c-Myc overexpression mirrored the response with HiMC. No additional effect of combining c-Myc overexpression and HiMC was observed. Conclusion: c-Myc overexpression is sufficient to stimulate skeletal muscle ribosome biogenesis and protein synthesis without activation of mTORC1. Therefore, the HiMC-induced increase in c-Myc may contribute to ribosome biogenesis and increased protein synthesis following HiMC.

scholarly journals The Effect of Cancer Cachexia Progression on the Feeding Regulation of Skeletal Muscle Protein Turnover

2021 ◽  
Author(s):  
◽  
Brittany Franch ◽  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Cancer Cachexia ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Skeletal Muscle Protein ◽  
Ampk Signaling ◽  
Tumor Bearing ◽  
Feeding Regulation ◽  
Mtorc1 Signaling

Cancer cachexia is defined as the unintentional loss of skeletal muscle mass with or without fat loss that cannot be reversed by conventional nutritional support. Cachexia occurs in ~20% of cancer patients. More specifically, 50% of lung cancer patients, the most common cancer worldwide, develop cachexia. Cachexia occurs most often in lung and gastrointestinal cancers, whereas breast and prostate have the lowest rate of cachexia. Cancer-induced cachexia disrupts skeletal muscle protein turnover (decreasing protein synthesis and increasing protein degradation). Skeletal muscle’s capacity for protein synthesis is highly sensitive to local and systemic stimuli that are controlled by mTORC1 and AMPK signaling. During cachexia, altered protein turnover is thought to occur through suppressed anabolic signaling via mTORC1, coinciding with the chronic activation of AMPK. While progress has been made in understanding some of the mechanisms underlying the suppressed anabolic signaling in cachectic muscle, gaps still remain in our understanding of muscle’s ability to respond to anabolic stimulus prior to cachexia development. The purpose of this study was to determine if cachexia progression disrupts the feeding regulation of AMPK signaling and if gp130 signaling and muscle contraction could regulate this process. Specific aim 1 examined the feeding regulation of skeletal muscle protein synthesis in pre-cachectic tumor bearing mice. Feeding increased muscle protein synthesis, while lowering AMPK signaling in pre-cachectic tumor bearing mice. Importantly, pre-cachectic tumor bearing mice have overall suppressed muscle protein synthesis independent of the fast or fed condition. Muscle specific AMPK loss was sufficient to improve the fasting suppression of muscle mTORC1 and protein synthesis in pre-cachectic tumor bearing mice. Specific aim 2 examined if muscle gp130 signaling regulates the feeding regulation of AMPK during cancer cachexia progression. Muscle gp130 loss lowered the fasting induction of AMPK in pre-cachectic tumor bearing mice without improving protein synthesis. Muscle gp130 loss did not alter the feeding regulation of muscle Akt/mTORC1 signaling and protein synthesis. Specific Aim 3 examined if an acute bout of muscle contractions could improve the muscle protein synthesis response to feeding during the progression of cachexia. Pre-cachectic tumor bearing mice exhibit suppressed protein synthesis in response low frequency electrical stimulation, and the inability to synergistically induce protein synthesis in response to feeding and contraction. In summary, pre-cachectic tumor bearing mice have lowered Akt/mTORC1 signaling and protein synthesis. Feeding can induce Akt/mTORC1 and protein synthesis and AMPK regulates the fasting suppression of protein synthesis in pre-cachectic tumor bearing mice. While gp130 loss reduces AMPK it is not sufficient to improve protein synthesis in pre-cachectic tumor bearing mice. The added protein synthesis response to feeding and contraction is blunted in pre-cachectic tumor bearing mice. These findings provide novel insight into the regulation of Akt/mTORC1 signaling and protein synthesis in response to feeding. Additionally, these studies highlight gp130’s regulation of AMPK prior to cachexia development, and the blunted anabolic muscle response to feeding and contraction in pre-cachectic tumor bearing mice. By understanding these intracellular signaling processes and perturbations prior to cachexia development, we will be able to elucidate potential therapeutic targets and treatment options to manipulate and prevent cancer cachexia.

scholarly journals Leucine or carbohydrate supplementation reduces AMPK and eEF2 phosphorylation and extends postprandial muscle protein synthesis in rats

2011 ◽  
Vol 301 (6) ◽  
pp. E1236-E1242 ◽  
Author(s):  
Gabriel J. Wilson ◽  
Donald K. Layman ◽  
Christopher J. Moulton ◽  
Layne E. Norton ◽  
Tracy G. Anthony ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Test Meal ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Adenosine Monophosphate ◽  
Energy Status ◽  
Sprague Dawley ◽  
Translation Elongation ◽  
Cellular Energy ◽  
Mtorc1 Signaling

Muscle protein synthesis (MPS) increases after consumption of a protein-containing meal but returns to baseline values within 3 h despite continued elevations of plasma amino acids and mammalian target of rapamycin (mTORC1) signaling. This study evaluated the potential for supplemental leucine (Leu), carbohydrates (CHO), or both to prolong elevated MPS after a meal. Male Sprague-Dawley rats (∼270 g) trained to consume three meals daily were food deprived for 12 h, and then blood and gastrocnemius muscle were collected 0, 90, or 180 min after a standard 4-g test meal (20% whey protein). At 135 min postmeal, rats were orally administered 2.63 g of CHO, 270 mg of Leu, both, or water (sham control). Following test meal consumption, MPS peaked at 90 min and then returned to basal ( time 0) rates at 180 min, although ribosomal protein S6 kinase and eIF4E-binding protein-1 phosphorylation remained elevated. In contrast, rats administered Leu and/or CHO supplements at 135 min postmeal maintained peak MPS through 180 min. MPS was inversely associated with the phosphorylation states of translation elongation factor 2, the “cellular energy sensor” adenosine monophosphate-activated protein kinase-α (AMPKα) and its substrate acetyl-CoA carboxylase, and increases in the ratio of AMP/ATP. We conclude that the incongruity between MPS and mTORC1 at 180 min reflects a block in translation elongation due to reduced cellular energy. Administering Leu or CHO supplements ∼2 h after a meal maintains cellular energy status and extends the postprandial duration of MPS.

scholarly journals Higher skeletal muscle protein synthesis and lower breakdown after chemotherapy in cachectic mice

2001 ◽  
Vol 281 (1) ◽  
pp. R133-R139 ◽  
Author(s):  
S. E. Samuels ◽  
A. L. Knowles ◽  
T. Tilignac ◽  
E. Debiton ◽  
J. C. Madelmont ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Muscle Mass ◽  
Skeletal Muscle Mass ◽  
Cancer Cachexia ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Human Condition ◽  
Skeletal Muscle Protein ◽  
Tumor Bearing

The influence of cancer cachexia and chemotherapy and subsequent recovery of skeletal muscle protein mass and turnover was investigated in mice. Cancer cachexia was induced using colon 26 adenocarcinoma, which is characteristic of the human condition, and can be cured with 100% efficacy using an experimental nitrosourea, cystemustine (C6H12CIN3O4S). Reduced food intake was not a factor in these studies. Three days after cachexia began, healthy and tumor-bearing mice were given a single intraperitoneal injection of cystemustine (20 mg/kg). Skeletal muscle mass in tumor-bearing mice was 41% lower ( P < 0.05) than in healthy mice 2 wk after cachexia began. Skeletal muscle wasting was mediated initially by decreased protein synthesis (−38%; P < 0.05) and increased degradation (+131%; P < 0.05); later wasting resulted solely from decreased synthesis (∼−54 to −69%; P < 0.05). Acute cytotoxicity of chemotherapy did not appear to have an important effect on skeletal muscle protein metabolism in either healthy or tumor-bearing mice. Recovery began 2 days after treatment; skeletal muscle mass was only 11% lower than in healthy mice 11 days after chemotherapy. Recovery of skeletal muscle mass was affected initially by decreased protein degradation (−80%; P < 0.05) and later by increased protein synthesis (+46 to +73%; P < 0.05) in cured compared with healthy mice. This study showed that skeletal muscle wasted from cancer cachexia and after chemotherapeutic treatment is able to generate a strong anabolic response by making powerful changes to protein synthesis and degradation.

scholarly journals Insulin Stimulates Human Skeletal Muscle Protein Synthesis via an Indirect Mechanism Involving Endothelial-Dependent Vasodilation and Mammalian Target of Rapamycin Complex 1 Signaling

2010 ◽  
Vol 24 (6) ◽  
pp. 1306-1306
Author(s):  
Kyle L. Timmerman ◽  
Jessica L. Lee ◽  
Hans C. Dreyer ◽  
Shaheen Dhanani ◽  
Erin L. Glynn ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Mammalian Target Of Rapamycin ◽  
Skeletal Muscle Protein ◽  
Capillary Recruitment ◽  
Isotope Tracers ◽  
Skeletal Muscle Protein Synthesis ◽  
Mtorc1 Signaling

Abstract Objective: Our objective was to determine whether endothelial-dependent vasodilation is an essential mechanism by which insulin stimulates human skeletal muscle protein synthesis and anabolism. Subjects: Subjects were healthy young adults (n = 14) aged 31 ± 2 yr. Design: Subjects were studied at baseline and during local leg infusion of insulin alone (control, n = 7) or insulin plus the nitric oxide synthase inhibitor NG-monomethyl-l-arginine (L-NMMA, n = 7) to prevent insulin-induced vasodilation. Methods: We measured skeletal muscle protein metabolism with stable isotope tracers, blood flow with indocyanine green, capillary recruitment with contrast enhanced ultrasound, glucose metabolism with stable isotope tracers, and phosphorylation of proteins associated with insulin (Akt) and amino acid-induced mammalian target of rapamycin(mTOR) complex 1 (mTORC1) signaling (mTOR, S6 kinase 1, and eukaryotic initiation factor 4Ebinding protein 1) with Western blot analysis. Results: No basal differences between groups were detected. During insulin infusion, blood flow and capillary recruitment increased in the control (P &lt; 0.05) group only; Akt phosphorylation and glucose uptake increased in both groups (P &lt; 0.05), with no group differences; and mTORC1 signaling increased more in control (P &lt; 0.05) than in l-NMMA. Phenylalanine net balance increased (P &lt; 0.05) in both groups, but with opposite mechanisms: increased protein synthesis (basal, 0.051 ± 0.006%/h; insulin, 0.077 ± 0.008%/h; P &lt; 0.05) with no change in proteolysis in control and decreased proteolysis (P &lt; 0.05) with no change in synthesis (basal, 0.061 ± 0.004%/h; insulin, 0.050 ± 0.006%/h; P value not significant) in l-NMMA. Conclusions: Endothelial-dependent vasodilation and the consequent increase in nutritive flow and mTORC1 signaling, rather than Akt signaling, are fundamental mechanisms by which insulin stimulates muscle protein synthesis in humans. Additionally, these data underscore that insulin modulates skeletal muscle proteolysis according to its effects on nutritive flow.

scholarly journals Activation of mTORC1 signaling and protein synthesis in human muscle following blood flow restriction exercise is inhibited by rapamycin

2014 ◽  
Vol 306 (10) ◽  
pp. E1198-E1204 ◽  
Author(s):  
David M. Gundermann ◽  
Dillon K. Walker ◽  
Paul T. Reidy ◽  
Michael S. Borack ◽  
Jared M. Dickinson ◽  
...  
Keyword(s):  
Blood Flow ◽  
Protein Synthesis ◽  
Time Course ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Vastus Lateralis ◽  
Human Muscle ◽  
Leg Extension ◽  
Or Groups ◽  
Mtorc1 Signaling

Restriction of blood flow to a contracting muscle during low-intensity resistance exercise (BFR exercise) stimulates mTORC1 signaling and protein synthesis in human muscle within 3 h postexercise. However, there is a lack of mechanistic data to provide a direct link between mTORC1 activation and protein synthesis in human skeletal muscle following BFR exercise. Therefore, the primary purpose of this study was to determine whether mTORC1 signaling is necessary for stimulating muscle protein synthesis after BFR exercise. A secondary aim was to describe the 24-h time course response in muscle protein synthesis and breakdown following BFR exercise. Sixteen healthy young men were randomized to one of two groups. Both the control (CON) and rapamycin (RAP) groups completed BFR exercise; however, RAP was administered 16 mg of the mTOR inhibitor rapamycin 1 h prior to BFR exercise. BFR exercise consisted of four sets of leg extension exercise at 20% of 1 RM. Muscle biopsies were collected from the vastus lateralis before exercise and at 3, 6, and 24 h after BFR exercise. Mixed-muscle protein fractional synthetic rate increased by 42% at 3 h postexercise and 69% at 24 h postexercise in CON, whereas this increase was inhibited in the RAP group. Phosphorylation of mTOR (Ser2448) and S6K1 (Thr389) was also increased in CON but inhibited in RAP. Mixed-muscle protein breakdown was not significantly different across time or groups. We conclude that activation of mTORC1 signaling and protein synthesis in human muscle following BFR exercise is inhibited in the presence of rapamycin.

High-intensity muscle contraction-mediated increases in Akt1 and Akt2 phosphorylation do not contribute to mTORC1 activation and muscle protein synthesis

2020 ◽  
Vol 128 (4) ◽  
pp. 830-837 ◽  
Author(s):  
Yuki Maruyama ◽  
Chisaki Ikeda ◽  
Koki Wakabayashi ◽  
Satoru Ato ◽  
Riki Ogasawara
Keyword(s):  
Protein Synthesis ◽  
Resistance Exercise ◽  
Muscle Contraction ◽  
High Intensity ◽  
Gastrocnemius Muscle ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Target Of Rapamycin ◽  
Mechanistic Target Of Rapamycin ◽  
Mtorc1 Activation

High-intensity muscle contraction (HiMC) is known to induce muscle protein synthesis, a process in which mechanistic target of rapamycin (mTOR) is reported to play a critical role. However, the mechanistic details have not been completely elucidated. Here, we investigated whether Akt plays a role in regulating HiMC-induced mTORC1 activation and muscle protein synthesis using a rodent model of resistance exercise and MK2206 (an Akt kinase inhibitor). The right gastrocnemius muscle of male C57BL/6J mice aged 10 wk was isometrically contracted via percutaneous electrical stimulation (100 Hz, 5 sets of 10 3-s contractions, 7-s rest between contractions, and 3-min rest between sets), while the left gastrocnemius muscle served as a control. Vehicle or MK2206 was injected intraperitoneally 6 h before contraction. MK2206 inhibited both resting and HiMC-induced phosphorylation of Akt1 Ser-473 and Akt2 Ser-474. MK2206 also inhibited the resting phosphorylation of p70S6K and 4E-BP1, which are downstream targets of mTORC1; however, it did not inhibit the HiMC-induced increase in phosphorylation of these targets. Similarly, MK2206 inhibited the resting muscle protein synthesis, but not the resistance exercise-induced muscle protein synthesis. On the basis of these observations, we conclude that although Akt2 regulates resting mTORC1 activity and muscle protein synthesis, HiMC-induced increases in mTORC1 activity and muscle protein synthesis are Akt-independent processes. NEW & NOTEWORTHY Akt is well known to be an upstream regulator of mechanistic target of rapamycin (mTOR) and has three isoforms in mammals, namely, Akt1, Akt2, and Akt3. We found that high-intensity muscle contraction (HiMC) increases Akt1 and Akt2 phosphorylation; however, HiMC-induced increases in mTORC1 activity and muscle protein synthesis are Akt-independent processes.

scholarly journals Repeated eccentric contractions positively regulate muscle oxidative metabolism and protein synthesis during cancer cachexia in mice

2020 ◽  
Vol 128 (6) ◽  
pp. 1666-1676 ◽  
Author(s):  
Justin P. Hardee ◽  
Dennis K. Fix ◽  
Ho-Jin Koh ◽  
Xuewen Wang ◽  
Edie C. Goldsmith ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Oxidative Metabolism ◽  
Cancer Cachexia ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Eccentric Contraction ◽  
Oxidative Capacity ◽  
Preclinical Model ◽  
Metabolic Plasticity ◽  
Mitochondrial Homeostasis

Cancer-induced muscle wasting is accompanied by disruptions to muscle oxidative metabolism and protein turnover regulation, whereas exercise is a potent stimulator of muscle protein synthesis and mitochondrial homeostasis. In a preclinical model of cancer cachexia, we report that cachectic muscle retains anabolic and metabolic plasticity to repeated eccentric contraction bouts despite an overall systemic wasting environment. The attenuation of muscle atrophy is linked to improved oxidative capacity and protein synthesis during cancer cachexia progression.

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