Excessive eccentric exercise-induced overtraining model leads to endoplasmic reticulum stress in mice skeletal muscles

Pereira, Bruno; Rocha, Aristides Almeida; Pinto, Ana P.; Pauli, José Rodrigo; Souza, Cláudio Teodoro de; Cintra, Dennys Esper; Ropelle, Eduardo Rochete; Freitas, Ellen Cristini de; Zagatto, Alessandro Moura; Silva, Adelino Sánchez Ramos da

doi:10.1016/j.lfs.2015.12.037

Cited by 50 publications

(54 citation statements)

References 39 publications

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“…The markers of ER stress, such as BiP, GRP94, GADD34, ATF4, CHOP, and sXBP1, are increased in skeletal muscle after a single bout of exhaustive treadmill running . Moreover, the levels of phosphorylated IRE1α, PERK, and eIF2α have been found to be elevated in the skeletal muscle of mice after a downhill treadmill running . The activation of the UPR appears to be an adaptive mechanism because, the mice that were previously trained to the exercise paradigm showed upregulation of only BiP and GRP94 in skeletal muscle during successive exercise training .…”

Section: Skeletal Muscle Remodelingmentioning

confidence: 99%

ER stress in skeletal muscle remodeling and myopathies

2017

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Skeletal muscle is a highly plastic tissue in the human body that undergoes extensive adaptation in response to environmental cues, such as physical activity, metabolic perturbation, and disease conditions. The endoplasmic reticulum (ER) plays a pivotal role in protein folding and calcium homeostasis in many mammalian cell types, including skeletal muscle. However, overload of misfolded or unfolded proteins in the ER lumen cause stress, which results in the activation of a signaling network called the unfolded protein response (UPR). The UPR is initiated by three ER transmembrane sensors: protein kinase R‐like endoplasmic reticulum kinase, inositol‐requiring protein 1α, and activating transcription factor 6. The UPR restores ER homeostasis through modulating the rate of protein synthesis and augmenting the gene expression of many ER chaperones and regulatory proteins. However, chronic heightened ER stress can also lead to many pathological consequences including cell death. Accumulating evidence suggests that ER stress‐induced UPR pathways play pivotal roles in the regulation of skeletal muscle mass and metabolic function in multiple conditions. They have also been found to be activated in skeletal muscle under catabolic states, degenerative muscle disorders, and various types of myopathies. In this article, we have discussed the recent advancements toward understanding the role and mechanisms through which ER stress and individual arms of the UPR regulate skeletal muscle physiology and pathology.

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Section: Skeletal Muscle Remodelingmentioning

confidence: 99%

ER stress in skeletal muscle remodeling and myopathies

2017

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“…However, in response to concurrent training programs, both proteins may be activated at the same time (Coffey et al, ; Wang et al, ). Based on this information and knowing the damage characteristics of the OTR/down model (da Rocha et al, , ; Pereira et al, ,,, ), the up‐regulation of pAMPK (Thr172) and pmTOR (Ser2448) may be considered a particularity of this specific OT protocol.…”

Section: Discussionmentioning

confidence: 99%

Exhaustive Training Leads to Hepatic Fat Accumulation

Rocha

Pinto

Teixeira

et al. 2017

Journal Cellular Physiology

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Recently, we demonstrated that an overtraining (OT) protocol for mice based on downhill running sessions increased the hepatic phosphorylation of 70-kDa ribosomal protein S6 kinase 1 (S6K1; Thr389), a downstream target of the mammalian target of rapamycin complex 1 (mTORC1). In liver, the overactivation of the Akt/mTORC1 pathway induces lipogenesis via regulation of the action of sterol regulatory element binding protein-1 (SREBP-1) at multiple steps. Herein, we verified the effects of three running OT models with same external load (i.e., the product between intensity and volume of training), but performed in downhill, uphill and without inclination, on the proteins related to the mTORC1 signaling pathway, the protein content of the SREBP-1, ACC, and FAS, and the morphological characteristics of C57BL/6 mouse livers. In summary, the downhill running-induced OT model up-regulated the levels of major proteins of the mTORC1 signaling pathway, the protein levels of SREBP-1 (p125 precursor) and induced signs of cell swelling accompanied by acute inflammation. The other two OT protocols performed uphill and without inclination did not modulate the most analyzed molecular proteins, but induced hepatic morphological alterations, suggesting an acute pathological adaptation. The three OT models induced hepatic fat accumulation. J. Cell. Physiol. 232: 2094-2103, 2017. © 2016 Wiley Periodicals, Inc.

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“…Future studies using flow cytometry will be useful to precisely determine the role of ATF3 on leukocyte infiltration. Downhill running is an effective model of overtraining in rodents, decreasing exercise performance and altering body mass [28]. Since ATF3-KO mice had a higher inflammation upon eccentric exercise, we tested whether they responded worse to repeated eccentric sessions.…”

Section: Discussionmentioning

confidence: 99%

Activating transcription factor 3 regulates chemokine expression in contracting C2C12 myotubes and in mouse skeletal muscle after eccentric exercise

Fernández‐Verdejo

Vanwynsberghe

Hai

et al. 2017

Biochemical and Biophysical Research Communications

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a b s t r a c tActivating transcription factor (ATF) 3 regulates chemokine expression in various cell types and tissues. Herein, we studied this regulation in contracting muscle cells in vitro, and in skeletal muscle after muscle-damaging exercise in vivo. C 2 C 12 myotubes with normal or low ATF3 levels (atf3_siRNA) were electrically stimulated (EPS). Also, ATF3-knockout (ATF3-KO) and control mice ran downhill until exhaustion, and muscles were analyzed post-exercise. EPS increased ATF3 levels in myotubes (P < 0.01). Chemokine C-C motif ligand (ccl) 2 mRNA increased post-EPS, but atf3_siRNA attenuated the response (P < 0.05). Atf3_siRNA up-regulated ccl6 basal mRNA, and down-regulated ccl9 and chemokine C-X-C motif ligand (cxcl) 1 basal mRNAs. Post-exercise, ATF3-KO mice showed exacerbated mRNA levels of ccl6 and ccl9 in soleus (P < 0.05), and similar trends were observed for ccl2 and interleukin (il) 1b (P < 0.09). In quadriceps, il6 mRNA level increased only in ATF3-KO (P < 0.05), and cxcl1 mRNA showed a similar trend (P ¼ 0.082). Cluster of differentiation-68 (cd68) mRNA, a macrophage marker, increased in quadriceps and soleus independently of genotype (P < 0.001). Our data demonstrate that ATF3 regulates chemokine expression in muscle cells in vitro and skeletal muscle in vivo, but the regulation differs in each model. Cells other than myofibers may thus participate in the response observed in skeletal muscle. Our results also indicate that ATF3-independent mechanisms would regulate macrophage infiltration upon muscledamaging exercise. The implications of chemokine regulation in skeletal muscle remain to be determined.

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Excessive eccentric exercise-induced overtraining model leads to endoplasmic reticulum stress in mice skeletal muscles

Abstract: The above findings suggest that the OTR/down protocol-induced skeletal muscle ER stress may be linked to a pathological condition in EDL and soleus muscles.

Cited by 50 publications

References 39 publications

ER stress in skeletal muscle remodeling and myopathies

ER stress in skeletal muscle remodeling and myopathies

Exhaustive Training Leads to Hepatic Fat Accumulation

Activating transcription factor 3 regulates chemokine expression in contracting C2C12 myotubes and in mouse skeletal muscle after eccentric exercise

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