Changes in UPR-PERK pathway and muscle hypertrophy following resistance training and creatine supplementation in rats


The unfolded protein response (UPR) plays a pivotal role in some exercise training–induced physiological adaptation. Our aim was to evaluate the changes in the protein kinase R-like endoplasmic reticulum kinase (PERK) arm of the UPR and hypertrophy signaling pathway following 8 weeks of resistance training and creatine (Cr) supplementation in rats. Thirty-two adult male Wistar rats (8 weeks old) were randomly divided into 4 groups of 8: untrained + placebo (UN+P), resistance training + placebo (RT+P), untrained + Cr (UN+Cr), and resistance training + Cr (RT+Cr). Trained animals were submitted to the ladder-climbing exercise training 5 days per week for a total of 8 weeks. Cr supplementation groups received creatine diluted with 1.5 ml of 5% dextrose orally. The flexor hallucis longus (FHL) muscle was extracted 48 h after the last training session and used for western blotting. After training period, the RT+Cr and RT+P groups presented a significant increase in phosphorylated and phosphorylated/total ratio hypertrophy indices, phosphorylated and phosphorylated/total ratio PERK pathway proteins, and other downstream proteins of the PERK cascade compared with their untrained counterparts (P < 0.05). The increase in hypertrophy indices were higher but PERK pathway proteins were lower in the RT-Cr group than in the RT+P group (P < 0.05). There was no significant difference between the untrained groups (P > 0.05). Our study suggests that resistance training in addition to Cr supplementation modifies PERK pathway response and improves skeletal muscle hypertrophy.

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This research work was financially supported by the University of Kurdistan, Sanandaj, Iran (grant number: 17873).

Author information




Hersh N and Dariush SH-V performed the experiments, analyzed the data, and drafted the manuscript. Dariush SH-V designed the research. Mohammad Raman M conducted the histological assays and participated in the writing of the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

Corresponding author

Correspondence to Dariush Sheikholeslami-Vatani.

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Ethics approval

Animals used in the current research were treated in accordance with the National Institutes of Health Guide for the care and use of laboratory animals, and the study design was reviewed and approved by the Animal Research Ethics Committee of Kurdistan University of Medical Sciences (IR.MUK.REC.1397.5010).

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The authors declare no competing interests.

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Key Points

Creatine has a synergistic effect on hypertrophy caused by resistance training.

Resistance training increases phosphorylates PERK proteins and its downstream pathway.

Creatine supplementation during resistance training modifies PERK pathway response.

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Nouri, H., Sheikholeslami-Vatani, D. & Moloudi, M.R. Changes in UPR-PERK pathway and muscle hypertrophy following resistance training and creatine supplementation in rats. J Physiol Biochem 77, 331–339 (2021).

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  • Ladder-climbing training
  • UPR
  • PERK pathway
  • Muscle mass
  • Creatine