PERK regulates skeletal muscle mass and contractile function in adult mice
Open accessAbstract
Skeletal muscle mass is regulated by the coordinated activation of several anabolic and catabolic pathways. The endoplasmic reticulum (ER) is a major site of protein folding and a reservoir for calcium ions. Accretion of misfolded proteins or depletion in calcium concentration causes stress in the ER, which leads to the activation of a signaling network known as the unfolded protein response (UPR). In the present study, we investigated the role of the protein kinase R‐like endoplasmic reticulum kinase (PERK) arm of the UPR in the regulation of skeletal muscle mass and function in naive conditions and in a mouse model of cancer cachexia. Our results demonstrate that the targeted inducible deletion of PERK reduces skeletal muscle mass, strength, and force production during isometric contractions. Deletion of PERK also causes a slow‐to‐fast fiber type transition in skeletal muscle. Furthermore, short hairpin RNA‐mediated knockdown or pharmacologic inhibition of PERK leads to atrophy in cultured myotubes. While increasing the rate of protein synthesis, the targeted deletion of PERK leads to the increased expression of components of the ubiquitin‐proteasome system and autophagy in skeletal muscle. Ablation of PERK also increases the activation of calpains and deregulates the gene expression of the members of the FGF19 subfamily. Furthermore, the targeted deletion of PERK increases muscle wasting in Lewis lung carcinoma tumor‐bearing mice. Our findings suggest that the PERK arm of the UPR is essential for the maintenance of skeletal muscle mass and function in adult mice.—Gallot, Y. S., Bohnert, K. R., Straughn, A. R., Xiong, G., Hindi, S. M., Kumar, A., PERK regulates skeletal muscle mass and contractile function in adult mice. FASEB J. 33, 1946–1962 (2019). www.fasebj.org
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Both inducible inhibition or knockdown of PERK in muscle and myotubes resulted in atrophy due to upregulation of autophagy and ubiquitin-proteasome genes.
“Both inducible inhibition or knockdown of PERK in muscle and myotubes resulted in atrophy due to upregulation of autophagy and ubiquitin–proteasome genes75.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [75]
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“evidence suggesting the relevance of the PERK arm of the unfolded protein response to the maintenance of muscle mass and function has been reported (Gallot et al., 2018).”
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Self-citationPERK Signaling Controls Myoblast Differentiation by Regulating MicroRNA Networks
Tan, Y.-Y., Zhang, Y., Li, B., Ou, Y.-W., Xie, S., Chen, P.-P., Mei, S.-Q., Huang, Q.-J., Zheng, L., & Qu, L. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.670435 · Cited by 20 · see citing works
Neyroud, D., D’Lugos, A. C., Trevino, E. J., Callaway, C. S., Lamm, J. H., Laitano, O., Poole, B., Deyhle, M. R., Brantley, J., Le, L., et al. (2025) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.13668 · Cited by 19 · see citing works
“Although targeted ablation of the PERK arm of the UPR exacerbates cancer cachexia in mice [39], inhibition of XBP1, a downstream target of TLR-MYD88 signalling and the IRE1α arm of the UPR ameliorated cancer-induced muscle wasting [40].”
Zhong, P., Li, X., & Li, J. (2025) · Frontiers in Oncology · doi:10.3389/fonc.2025.1551561 · Cited by 18 · see citing works
“Deletion of PERK in tumor-bearing mice has been shown to worsen muscle atrophy, with increased activation of ubiquitin-proteasome and autophagy pathways in skeletal muscle (164).”
Signaling networks governing skeletal muscle growth, atrophy, and cachexia
Joshi, A. S., da Silva, M. T., Kumar, S., & Kumar, A. (2025) · Skeletal Muscle · doi:10.1186/s13395-025-00397-z · Cited by 20 · see citing works
“…leading to reduced muscle mass, grip strength, muscle contractile force production during isometric contractions, and exacerbation of muscle atrophy in Lewis lung carcinoma (LLC) tumor-bearing mice suggesting that PERK is important for maintaining skeletal muscle mass in adult animals [150].”
Self-citationWithaferin A and Ovarian Cancer Antagonistically Regulate Skeletal Muscle Mass
Straughn, A. R., Kelm, N., & Kakar, S. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.636498 · Cited by 15 · see citing works
Self-citationMyD88-mediated signaling intercedes in neurogenic muscle atrophy through multiple mechanisms
Parveen, A., Bohnert, K. R., da Silva, M. T., Wen, Y.-F., Bhat, R., Roy, A., & Kumar, A. (2021) · The FASEB Journal · doi:10.1096/fj.202100777rr · Cited by 15 · see citing works
Self-citationCancer-associated muscle weakness - From triggers to molecular mechanisms
Shorter, E., Engman, V., & Lanner, J. T. (2024) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2024.101260 · Cited by 16 · see citing works
TAK1 preserves skeletal muscle mass and mitochondrial function through redox homeostasis
Roy, A., Sharma, A. K., Nellore, K., Narkar, V. A., & Kumar, A. (2020) · FASEB BioAdvances · doi:10.1096/fba.2020-00043 · Cited by 15 · see citing works
Self-citationZhao, H., Chong, J., Li, D., & Xia, J. (2022) · Aquaculture · doi:10.1016/j.aquaculture.2022.738808 · Cited by 15 · see citing works
LncRNAs and CircRNAs in Endoplasmic Reticulum Stress: A Promising Target for Cardiovascular Disease?
Martínez-Amaro, F. J., García‐Padilla, C., Franco, D., & Daimi, H. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24129888 · Cited by 15 · see citing works
Hentilä, J., Nissinen, T. A., Korkmaz, A., Lensu, S., Silvennoinen, M., Pasternack, A. H., Ritvos, O., Atalay, M., & Hulmi, J. J. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2018.01917 · Cited by 14 · see citing works
Chaudhary, P., Sharma, S., Singh, R., & Arya, R. (2021) · Journal of Cellular Biochemistry · doi:10.1002/jcb.30148 · Cited by 13 · see citing works
“Inhibition of PERK signaling has been shown to reduce neurodegeneration and improved motor activity required for maintenance of skeletal muscle mass.(75,76) Also, enhanced PERK signaling has been shown to halt the synthesis of crucial proteins required for neuronal health.”
BackgroundThe IRE1α Arm of UPR Regulates Muscle Cells Immune Characters by Restraining p38 MAPK Activation
Gu, R.-C., Huang, T., Xiao, J.-W., Liao, Z.-H., Li, J., Lan, H.-Y., Ouyang, J., Hu, J., & Liao, H. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.01198 · Cited by 10 · see citing works
Chaudhari, M., Zelko, I. N., Lorkiewicz, P. K., Hoetker, D., Nong, Y., Doelling, B., Brittian, K. R., Bhatnagar, A., Srivastava, S., & Baba, S. P. (2024) · Skeletal Muscle · doi:10.1186/s13395-024-00354-2 · Cited by 12 · see citing works
“Grip strength measurements were performed as described previously [38, 39].”
MethodPagliara, V., Donadio, G., Tommasi, N. D., Amodio, G., Remondelli, P., Moltedo, O., & Piaz, F. D. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21197186 · Cited by 12 · see citing works
“The mean diameter per myotube was calculated as the means of the 3 measurements taken along the length of the myotube [39].”
MethodXiao, J.-W., Huang, J., Jian, X., Wang, H., Lan, H.-Y., Liao, Z.-H., Gu, R.-C., Hu, J., & Liao, H. (2023) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-023-00429-w · Cited by 9 · see citing works
“In addition, the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) arm of UPR has been reported to prevent loss of muscle mass and strength caused by cancer cachexia [10, 11].”
BackgroundThe TWEAK/Fn14 signaling mediates skeletal muscle wasting during cancer cachexia
da Silva, M. T., Roy, A., Vuong, A. T., Joshi, A. S., Josphien, C., Trivedi, M. V., Hindi, S. M., Narkar, V. A., & Kumar, A. (2025) · iScience · doi:10.1016/j.isci.2025.112714 · Cited by 11 · see citing works
“14,59 However, chronic activation of ER-stress-induced UPR can cause deleterious consequences in skeletal muscle.”
Self-citationAll-trans retinoic acid changes muscle fiber type via increasing GADD34 dependent on MAPK signal
Adachi, Y., Masuda, M., Sakakibara, I., Uchida, T., Niida, Y., Mori, Y., Kamei, Y., Okumura, Y., Ohminami, H., Ohnishi, K., et al. (2022) · Life Science Alliance · doi:10.26508/lsa.202101345 · Cited by 11 · see citing works
Harada, N., Gotoda, Y., Hatakeyama, A., Nakagawa, T., Miyatake, Y., Kuroda, M., Masumoto, S., Tsutsumi, R., Nakaya, Y., & Sakaue, H. (2020) · Journal of Muscle Research and Cell Motility · doi:10.1007/s10974-020-09582-7 · Cited by 10 · see citing works
Joshi, A. S., da Silva, M. T., Vuong, T. A., Xu, B., Singh, R. K., & Kumar, A. (2025) · EMBO Molecular Medicine · doi:10.1038/s44321-025-00337-w · Cited by 9 · see citing works
“It is now increasingly evidenced that individual arms of the UPR play distinct roles in the regulation of skeletal muscle physiology and pathophysiology (Afroze and Kumar, 2019; Gallot et al, 2019; Joshi et al, 2024b; Roy and Kumar, 2019).”
Self-citationNouri, H., Sheikholeslami‐Vatani, D., & Moloudi, M. R. (2021) · Journal of Physiology and Biochemistry · doi:10.1007/s13105-021-00801-4 · Cited by 9 · see citing works
Xiang, X., Zhu, Y., Pan, X., Xin, W., Chen, J., Tang, W., Guo, R., Yuan, W., He, X., Li, Z., et al. (2023) · Obesity · doi:10.1002/oby.23809 · Cited by 9 · see citing works
“reported to be essential for regulating the physiological function of skeletal muscle, including the regulation of satellite cell regeneration [41] and the maintenance of skeletal muscle mass and function [42].”
BackgroundEmerging role of TAK1 in the regulation of skeletal muscle mass
Roy, A., Narkar, V. A., & Kumar, A. (2023) · BioEssays · doi:10.1002/bies.202300003 · Cited by 8 · see citing works
Self-citationZhao, H., Iyama, R., Kurogi, E., Hayashi, T., & Egawa, T. (2024) · Physiological Reports · doi:10.14814/phy2.16121 · Cited by 8 · see citing works
“PERK has been reported to be essential for the maintenance of skeletal muscle mass in mice with cancer cachexia (Gallot et al., 2019).”
BackgroundRNA signaling in skeletal muscle: the central role of microRNAs and exosomal microRNAs
Liu, S., & Dong, H. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1639123 · Cited by 8 · see citing works
Effect of Denervation on XBP1 in Skeletal Muscle and the Neuromuscular Junction
Walter, L. A., Blake, L. P., Gallot, Y. S., Arends, C. J., Sozio, R. S., Onifer, S. M., & Bohnert, K. R. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms23010169 · Cited by 7 · see citing works
Self-citationLi, L., Wen, Y., Jiang, L., & Zhu, Y. (2021) · Archives of Oral Biology · doi:10.1016/j.archoralbio.2021.105312 · Cited by 6 · see citing works
Wu, B., Qiu, R., Wang, S., He, Y., Wang, J., Xu, Z., Lin, X., Li, H., & Zheng, F. (2023) · Journal of Molecular Endocrinology · doi:10.1530/jme-22-0163 · Cited by 4 · see citing works
Lin, S., Wu, J., Lian, G., Wu, W., Chen, W., Chen, A., Luo, L., & Xie, L. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1607606 · Cited by 3 · see citing works
“…mass and muscle atrophy, although knockout of PERK caused a decrease in the ratio of p-eIF2 α /eIF2 α and an increase in protein synthesis, it also induced the activation of the ubiquitin proteasome pathway, autophagy pathway, and ultimately caused skeletal muscle atrophy (Gallot et al., 2019).”
Yeo, D. (2025) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-88361-3_8 · Cited by 4 · see citing works
Chung, B., Jonas, W., Rostami, F., Malik, Z., Szaroszyk, M., Levay, M. K., Thackeray, J. T., Ost, M., Nowak, S., Hegermann, J., et al. (2025) · Cardiovascular Research · doi:10.1093/cvr/cvaf173 · Cited by 2 · see citing works
Investigation of the ubiquitin proteasome system in pulmonary arterial hypertensionPreprint
Li, Y., Bian, M., Gu, S., Wang, X., Wen, J., Lian, N., Jiang, M., & Xu, Q. (2023) · doi:10.22541/au.167991844.49422974/v1 · Cited by 2 · see citing works
Irisin: muscle’s novel player in endoplasmic reticulum stress and disease
Pinto, J. R., Bhat, K. D., Bose, B., & Sudheer Shenoy, P. (2025) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-025-05225-y · Cited by 1 · see citing works
“These findings showed that targeted inducible deletion of PERK decreases skeletal muscle morphological and functional outcomes [123] and results in atrophy of cultured myotubes, while in mice bearing LLC, skeletal muscle shows more components of the Ubiquitin–Proteasome System and…”
Liu, S., Xu, L., Song, X., Zhu, Z., Zhang, Y., Sun, Y., Nyoja, S., Wang, Q., Gao, J., Wang, L., et al. (2026) · Cell Stress and Chaperones · doi:10.1016/j.cstres.2026.100176 · Cited by 1 · see citing works
“7,8 9-11 Similarly, human placental tissue at Abbreviations: GRP78, glucose-regulated protein 78; ER, endoplasmic reticulum; UPR, unfolded protein response; FNDC5, fibronectin type III domain-containing protein 5; WGCNA, weighted gene co-expression network analysis; GSEA, gene set enrichment…”
da Silva, M. T., Joshi, A. S., Roy, A., Hornberger, T. A., & Kumar, A. (2026) · The FASEB Journal · doi:10.1096/fj.202601212r · Cited by 1 · see citing works
“Chronic ER stress and activation of the UPR can promote muscle atrophy by inhibiting protein synthesis and enhancing proteolysis [2, 30, 32, 38, 39].”
Self-citationSystemic and cardiac pathology induced by a clinically relevant USP8 activating mutation
González-Costa, T., Galicia-Martín, A., Calle, D., Cussó, L., Soto-Navarrete, M. T., Luo, X., Méndez-Peralta, L., Grego-Bessa, J., & de la Pompa, J. L. (2026) · Disease Models & Mechanisms · doi:10.1242/dmm.052695 · Cited by 1 · see citing works
“…in these transgenic mice is consistent with the established role of the ubiquitin – proteasome system (UPS) in maintaining skeletal muscle homeostasis (Bodine et al., 2001; Hunt et al., 2021), as well as with the reported increase in pERK signaling (Gallot et al., 2019; Miyake et al., 2017).”
Unfolded protein response pathways in skeletal muscle homeostasis.
Bohnert, K. R. (2018) · doi:10.18297/etd/3033
Self-citationCanonical nuclear factor-κB signaling in satellite stem cell homeostasis and function.
Straughn, A. R. (2018) · doi:10.18297/etd/3043
Self-citationAdachi, Y., Masuda, M., Sakakibara, I., Uchida, T., Niida, Y., Mori, Y., Kamei, Y., Okumura, Y., Ohminami, H., Ohnishi, K., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.10.04.463012
Marafon, B. B., Pinto, A. P., de Vicente, L. G., da Rocha, A. L., Simabuco, F. M., Ropelle, E. R., de Moura, L. P., Cintra, D. E., Pauli, J. R., & da Silva, A. S. R. (2022) · Cell Biochemistry and Function · doi:10.1002/cbf.3765
“Furthermore, PERK‐knockout mice also had muscle wasting and a reduction in contractile function.(44) Thus, the PERK arm is involved in many aspects of skeletal muscle physiology and pathophysiology.”
BackgroundAlmeida, L. M., Lima, L. P., Oliveira, N. A. S., Silva, R. F. O., Sousa, B., Bessa, J., Pinho, B. R., & Oliveira, J. M. A. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.04.16.589737
In Vivo Electroporation of Plasmid DNA into the Skeletal Muscle of Dystrophic Mouse Models
Lopez, M. A., Giarrano, G. N., & Weisleder, N. L. (2025) · Methods in molecular biology · doi:10.1007/978-1-0716-4811-7_15
Xiao, J., Huang, J., Jian, X., Wang, H., Lan, H., Liao, Z., Gu, R., Hu, J., & Liao, H. (2024) · Figshare · doi:10.6084/m9.figshare.26571703
Xiao, J., Huang, J., Jian, X., Wang, H., Lan, H., Liao, Z., Gu, R., Hu, J., & Liao, H. (2024) · Figshare · doi:10.6084/m9.figshare.26571700
Almeida, L. M., Lima, L. P., Oliveira, N. A. S., Silva, R. F. O., Sousa, B., Bessa, J., Pinho, B. R., & Oliveira, J. M. A. (2026) · Pharmacological Reports · doi:10.1007/s43440-026-00837-7
“Beyond pancreatic dysfunction, PERK inhibition in humans and mice impairs neuronal and muscular functions [5, 6, 11, 74, 75].”
Identification of new levers to fight muscle atrophy : benefit of the hibernating brown bear model
Cussonneau, L. (2022) · theses.fr (ABES) · doi:10.70675/1a11a81bzf829z4ba2zba9az6f3f4841c773
Mallard, J. (2022) · theses.fr (ABES) · doi:10.70675/f8b2c96bzc4cdz4249z8e59z5f87c7ca2462
Mitochondria–sarcoplasmic reticulum crosstalk as a modulator of skeletal muscle mass
Casuso, R. A. (2026) · Journal of Physiology and Biochemistry · doi:10.1007/s13105-026-01198-8
“Consistent with this dual role, PERK activity is required for the maintenance of SKM mass and function under basal conditions, whereas sustained ATF4 activity has been implicated in age-related reductions in skeletal muscle protein synthesis, strength, quality, and mass [37, 38].”
Ding, G., Yang, W., Zhao, Y., Liu, X., & Cui, J. (2026) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2026.189676
- Authors
- Gallot, Y. S., Bohnert, K. R., Straughn, A. R., Xiong, G., Hindi, S. M., & Kumar, A.
- Affiliations
- University of Louisville (US)
- Corresponding author
- Kumar, Ashok
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2018-09-11
- Volume
- 33
- Issue
- 2
- Pages
- 1946-1962
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- PMC
- PMC6338633
- OpenAlex
- W2890974598
- Cited by
- 67
- References
- 66
- Citations by year
- 2026: 6 · 2025: 12 · 2024: 6 · 2023: 6 · 2022: 8 · 2021: 13 · 2020: 5 · 2019: 9 · 2018: 2
- FWCI
- 2.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The FASEB Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AG029623, AR059810, AR068313)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
- Keywords
- PERK, unfolded protein response, skeletal muscle mass, muscle contractility, cancer cachexia, muscle atrophy, ubiquitin-proteasome system, autophagy, calpain activation, FGF19, muscle strength, Lewis lung carcinoma, endoplasmic reticulum stress
- MeSH terms
- Animals, Calpain, Cell Line, Mice, Knockout, Muscle Fibers, Fast-Twitch, Muscle Fibers, Slow-Twitch, eIF-2 Kinase, Ubiquitin, Proteasome Endopeptidase Complex, Mice, Unfolded Protein Response, Endoplasmic Reticulum Stress
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