The effects of physical exercise on insulin signaling and glycemic homeostasis are not yet fully understood. Recent findings elucidated the positive role of Rho‐kinase (Rock) in increasing the ...glucose uptake through insulin receptor substrate‐1 (IRS1) phosphorylation in the skeletal muscle. Here, we explored the effects of short‐term exercise on Rock activity and insulin signaling. Fischer 344 rats (3 months old) were subjected to a short‐term swimming exercise for 2 hr per day for 5 days, with an overload corresponding to 1.5% of body weight. As expected, the exercised group had a reduced glycemia and increased insulin sensitivity. The contents of Rock1, Rock2, and Rock activity were improved in the skeletal muscle of the exercised rats. The contents of RhoA and RhoGEF, which are proteins involved in the Rock metabolism, were also increased in the skeletal muscle after exercise. These changes in the protein contents were accompanied by an increase in the insulin signaling pathway (pIRS1/pPDK/pAkt/pGSK3β/pAS160/GLUT4), Rock activity, and IRS1 phosphorylation at the 632/635 serine residues. On the other hand, when Rock was inhibited with the Y‐27632, the insulin sensitivity in response to exercise was impaired. Based on these findings, we conclude that the short‐term exercise increased both insulin sensitivity and glucose tolerance, through the increased Rock activity and pIRS1 (serine 632/635) mediated by Rock, in the skeletal muscle of Fischer 344 rats. These data represent an exercise‐mediated novel mechanism, suggesting an essential role of Rock activity in the insulin signaling and glucose homeostasis improvement.
Short‐term physical exercise modulates Rock metabolism in skeletal muscle, and improves whole body glucose homeostasis and insulin sensitivity in rats. ‐ The exercised animals demonstrated increased Rock activity and IRS1 phosphorylation at S632/635 (Rock specific residue), as well as in insulin signaling pathway. ‐ This is the first study evaluating the role of physical exercise on Rock metabolism. Then, new therapeutic strategies to improve glucose homeostasis and prevent insulin resistance can be considered involving Rock protein.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The excessive eccentric exercise led to hepatic fat accumulation, which occurred concomitantly with elevation in the mammalian target of the rapamycin complex 1 (mTORC1) and insulin signaling ...pathways. Since mTORC1 and insulin can inhibit the autophagy pathway and explain the liver lipid content elevation, the main objective of the present investigation was to verify the responses of genes and proteins related to the autophagy and lipogenesis pathways in the hepatic tissue of mice submitted to the excessive downhill running protocol with and without rapamycin administration, a drug able to inhibit the mTORC1 pathway.
C57BL/6J mice were divided into four experimental groups: Control (CT; sedentary), Excessive exercise in downhill running (EE), Excessive exercise in downhill running with chronic administration of rapamycin (EE/Rapa), and Endurance exercise (END). At the end of the protocols, the blood and liver were collected for serum analysis, histology, immunohistochemistry, hepatic fat content, reverse transcription-quantitative polymerase chain reaction, and immunoblotting.
1) higher levels of glucose, insulin, HOMA-IR, cortisol, ALT, and cholesterol, but lower levels of T4 for the EE/Rapa group; 2) hepatic fat accumulation for the EE and EE/Rapa groups; 3) upregulation of LC3 immunoexpression and downregulation of autophagic flux index for the EE and EE/Rapa groups; 4) reduction of P70S6K phosphorylation and SQSTM1 and increase of FOXO1A phosphorylation for the EE/Rapa group.
The excessive exercise in downhill running with or without rapamycin led to increased liver fat content. Although rapamycin was effective in inhibiting mTORC1, the autophagy flux was not upregulated.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Strategies capable of attenuating TLR4 can attenuate metabolic processes such as inflammation, endoplasmic reticulum (ER) stress, and apoptosis in the body. Physical exercise has been a cornerstone ...in suppressing inflammation and dysmetabolic outcomes caused by TRL4 activation. Thus, the present study aimed to evaluate the effects of a chronic physical exercise protocol on the TLR4 expression and its repercussion in the inflammation, ER stress, and apoptosis pathways in mice hearts. Echocardiogram, RT-qPCR, immunoblotting, and histological techniques were used to evaluate the left ventricle of wild-type (WT) and Tlr4 knockout (TLR4 KO) mice submitted to a 4-week physical exercise protocol. Moreover, we performed a bioinformatics analysis to expand the relationship of Tlr4 mRNA in the heart with inflammation, ER stress, and apoptosis-related genes of several isogenic strains of BXD mice. The TLR4 KO mice had higher energy expenditure and heart rate in the control state but lower activation of apoptosis and ER stress pathways. The bioinformatics analysis reinforced these data. In the exercised state, the WT mice improved performance and cardiac function. However, these responses were blunted in the KO group. In conclusion, TLR4 has an essential role in the inhibition of apoptosis and ER stress pathways, as well as in the training-induced beneficial adaptations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Based on the crosstalk of inflammation with apoptosis, autophagy, and endoplasmic reticulum (ER) stress, the main objective of this study was to explore the role of interleukin-6 (IL-6) on genes and ...proteins related to these phenomena in the livers of mice submitted to acute exhaustive exercise.
Reverse transcription-quantitative polymerase chain reaction and immunoblotting technique were used to evaluate the livers of wild-type (WT) and IL-6 knockout (KO) mice at baseline (BL) and 3 h after the acute exhaustive physical exercise (EE).
Compared to the WT at baseline, the IL-6 KO had lower exhaustion velocity, mRNA levels of Mtor, Ulk1, Map1lc3b, and Mapk14, and protein contents of ATG5 and p-p70S6K/p70S6K. For the WT group, the EE decreased glycemia, mRNA levels of Casp3, Mtor, Ulk1, Foxo1a, Mapk14, and Ppargc1a, and protein contents of ATG5 and p-p70S6K/p70S6K, but increased mRNA levels of Sqstm1. For the IL-6 KO group, the EE decreased glycemia, mRNA levels of Casp3 and Foxo1a, and protein contents of pAkt/Akt and Mature/Pro IL-1beta, but increased mRNA levels of Sqstm1, and protein contents of p-AMPK/AMPK.
The inhibition of the hepatic autophagy markers induced by the acute EE was attenuated in IL-6 KO mice, highlighting a new function of this cytokine.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The endoplasmic reticulum (ER) stress and inflammation relationship occurs at different levels and is essential for the adequate homeostatic function of cellular systems, becoming harmful when ...chronically engaged. Intense physical exercise enhances serum levels of interleukin 6 (IL-6). In response to a chronic exhaustive physical exercise protocol, our research group verified an increase of the IL-6 concentration and ER stress proteins in extensor digitorium longus (EDL) and soleus. Based on these results, we hypothesized that IL-6-knockout mice would demonstrate a lower modulation in the ER stress proteins compared to the wild-type mice. To clarify the relationship between exercise-induced IL-6 increased and ER stress, we studied the effects of an acute exhaustive physical exercise protocol on the levels of ER stress proteins in the skeletal muscles of IL-6-knockout (KO) mice. The WT group displayed a higher exhaustion time compared to the IL-6 KO group. After 1 h of the acute exercise protocol, the serum levels of IL-6 and IL-10 were enhanced in the WT group. Independent of the experimental group, the CHOP and cleaved caspase 12/total caspase 12 ratio in EDL as well as ATF6 and CHOP in soleus were sensitive to the acute exercise protocol. Compared to the WT group, the oscillation patterns over time of BiP in EDL and soleus as well as of peIF2-alpha/eIF2-alpha ratio in soleus were attenuated for the IL-6 KO group. In conclusion, IL-6 seems to be related with the ER stress homeostasis, once knockout mice presented attenuation of BiP in EDL and soleus as well as of pEiF2-alpha/EiF2-alpha ratio in soleus after the acute exhaustive physical exercise protocol.
The present study verified the responses of proteins related to the autophagy pathway after 10 h of fast with resistance exercise and protein ingestion in skeletal muscle and liver samples. The rats ...were distributed into five experimental groups: control (CT; sedentary and without gavage after fast), exercise immediately (EXE-imm; after fast, rats were submitted to the resistance protocol and received water by gavage immediately after exercise), exercise after 1 h (EXE-1h; after fast, rats were submitted to the resistance protocol and received water by gavage 1 h after exercise), exercise and supplementation immediately after exercise (EXE/Suppl-imm; after fast, rats were submitted to the resistance protocol and received a mix of casein: whey protein 1:1 (
/
) by gavage immediately after exercise), exercise and supplementation 1 h after exercise (EXE/Suppl-1h; after fast, rats were submitted to the resistance protocol and received a mix of casein: whey protein 1:1 (
/
) by gavage 1 h after exercise). In summary, the current findings show that the combination of fasting, acute resistance exercise, and protein blend ingestion (immediately or 1 h after the exercise stimulus) increased the serum levels of leucine, insulin, and glucose, as well as the autophagy protein contents in skeletal muscle, but decreased other proteins related to the autophagic pathway in the liver. These results deserve further mechanistic investigations since athletes are combining fasting with physical exercise to enhance health and performance outcomes.
Interleukin-6 (IL-6) is associated with pathological cardiac hypertrophy and can be dramatically increased in serum after an acute strenuous exercise session. However, IL-6 is also associated with ...the increased production and release of anti-inflammatory cytokines and the inhibition of tumor necrosis factor-alpha (TNF-α) after chronic moderate exercise. To elucidate the relevance of IL-6 in inflammatory and hypertrophic signaling in the heart in response to an acute strenuous exercise session, we combined transcriptome analysis using the BXD mice database and exercised IL-6 knockout mice (IL-6KO). Bioinformatic analysis demonstrated that low or high-levels of Il6 mRNA in the heart did not change the inflammation- and hypertrophy-related genes in BXD mice strains. On the other hand, bioinformatic analysis revealed a strong positive correlation between Il6 gene expression in skeletal muscle with inflammation-related genes in cardiac tissue in several BXD mouse strains, suggesting that skeletal muscle-derived IL-6 could alter the heart's intracellular signals, particularly the inflammatory signaling. As expected, an acute strenuous exercise session increased IL-6 levels in wild-type, but not in IL-6KO mice. Despite not showing morphofunctional differences in the heart at rest, the IL-6KO group presented a reduction in physical performance and attenuated IL-6, TNF-α, and IL-1beta kinetics in serum, as well as lower p38MAPK phosphorylation, Ampkalpha expression, and higher Acta1 and Tnf gene expressions in the left ventricle in the basal condition. In response to strenuous exercise, IL-6 ablation was linked to a reduction in the pro-inflammatory response and higher activation of classical physiological cardiac hypertrophy proteins.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
29.
Exhaustive Training Leads to Hepatic Fat Accumulation da Rocha, Alisson L.; Pinto, Ana P.; Teixeira, Giovana R. ...
Journal of cellular physiology,
August 2017, 2017-Aug, 2017-08-00, 20170801, Volume:
232, Issue:
8
Journal Article
Exhaustive and chronic physical exercise leads to peripheral inflammation, which is one of the molecular mechanisms responsible for the impairment of the insulin signaling pathway in the heart. ...Recently, 3 different running overtraining models performed downhill (OTR/down), uphill (OTR/up), and without inclination (OTR) increased the serum levels of proinflammatory cytokines. This proinflammatory status induced insulin signaling impairment in the skeletal muscle; however, the response of this signaling pathway in the cardiac muscle of overtrained mice was still unknown. Thus, we investigated the effects of OTR/down, OTR/up, and OTR protocols on the protein levels of phosphorylation of insulin receptor β (pIRβ) (Tyr), phosphorylation of protein kinase B (pAkt) (Ser473), plasma membrane glucose transporter‐1 (GLUT1) and GLUT4, phosphorylation of insulin receptor substrate‐1 (pIRS‐1) (Ser307), phosphorylation of IκB kinase α/β) (pIKKα/β (Ser180/181), phosphorylation of p38 mitogen‐activated protein kinase (p‐p38MAPK) (Thr180/Tyr182), phosphorylation of stress‐activated protein kinases‐Jun amino‐terminal kinases (pSAPK‐JNK) (Thr183/Tyr185), and glycogen content in mice hearts. The rodents were divided into naïve (N, sedentary mice), control (CT, sedentary mice submitted to performance evaluations), trained (TR, performed the training protocol), OTR/down, OTR/up, and OTR groups. After the grip force test, the cardiac muscles (ie, left ventricle) were removed and used for immunoblotting and histology. Although the OTR/up and OTR groups exhibited higher cardiac levels of pIRβ (Tyr), only the OTR group exhibited higher cardiac levels of pAkt (Ser473) and plasma membrane GLUT4. On the contrary, the OTR/down group exhibited higher cardiac levels of pIRS‐1 (Ser307). The OTR model enhanced the cardiac insulin signaling pathway. All overtraining models increased the left ventricle glycogen content, with this probably acting as a compensatory organ in response to skeletal muscle insulin signaling impairment.
Schematic representation summarizing the current data.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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