Negative Impact of p21-Activated Kinase 4-Mediated AMP-Activated Protein Kinase Inhibition on Sarcopenia in Mice and Humans

Abstract

Clinical trial registration: Not applicable.

Keywords

AMPK / mitochondria / muscle atrophy / p21-activated kinase 4 / proteolysis-targeting chimera

References

[1] G. B. Kubat, E. Bouhamida, O. Ulger, et al., “Mitochondrial Dysfunction and Skeletal Muscle Atrophy: Causes, Mechanisms, and Treatment Strategies,” Mitochondrion 72 (2023): 33–58.

[2] F. Petermann-Rocha, V. Balntzi, S. R. Gray, et al., “Global Prevalence of Sarcopenia and Severe Sarcopenia: A Systematic Review and Meta-Analysis,” Journal of Cachexia, Sarcopenia and Muscle 13, no. 1 (2022): 86–99.

[3] A. T. Contillo, N. R. Rodriguez, and L. S. Pescatello, “Exercise and Protein Supplementation Recommendations for Older Adults With Sarcopenic Obesity: A Meta-Review,” Journal of Aging and Physical Activity 31, no. 5 (2023): 878–886.

[4] E. M. Crombie, S. Kim, S. Adamson, et al., “Activation of eIF4E-Binding-Protein-1 Rescues mTORC1-Induced Sarcopenia by Expanding Lysosomal Degradation Capacity,” Journal of Cachexia, Sarcopenia and Muscle 14, no. 1 (2023): 198–213.

[5] J. Xie, J. Hao, X. Xu, et al., “Identification of Association Between Mitochondrial Dysfunction and Sarcopenia Using Summary-Data-Based Mendelian Randomization and Colocalization Analyses,” Journals of Gerontology Series A, Biological Sciences and Medical Sciences 80, no. 4 (2025): glaf006.

[6] J. Wang, C. Cui, Y. N. Chim, et al., “Vibration and β-hydroxy-β-Methylbutyrate Treatment Suppresses Intramuscular Fat Infiltration and Adipogenic Differentiation in Sarcopenic Mice,” Journal of Cachexia, Sarcopenia and Muscle 11, no. 2 (2020): 564–577.

[7] F. Tanganelli, P. Meinke, F. Hofmeister, et al., “Type-2 Muscle fiber Atrophy Is Associated With Sarcopenia in Elderly Men With Hip Fracture,” Experimental Gerontology 144 (2021): 111171.

[8] S. Jager, C. Handschin, J. St-Pierre, and B. M. Spiegelman, “AMP-Activated Protein Kinase (AMPK) Action in Skeletal Muscle via Direct Phosphorylation of PGC-1α,” PNAS 104, no. 29 (2007): 12017–12022.

[9] D. T. Hall, T. Griss, J. F. Ma, et al., “The AMPK Agonist 5-Aminoimidazole-4-Carboxamide Ribonucleotide (AICAR), but Not Metformin, Prevents Inflammation-Associated Cachectic Muscle Wasting,” EMBO Molecular Medicine 10, no. 7 (2018): e8307.

[10] V. A. Narkar, M. Downes, R. T. Yu, et al., “AMPK and PPARdelta Agonists Are Exercise Mimetics,” Cell 134, no. 3 (2008): 405–415.

[11] C. Canto, Z. Gerhart-Hines, J. N. Feige, et al., “AMPK Regulates Energy Expenditure by Modulating NAD⁺ Metabolism and SIRT1 Activity,” Nature 458, no. 7241 (2009): 1056–1060.

[12] B. J. Krawiec, G. J. Nystrom, R. A. Frost, L. S. Jefferson, and C. H. Lang, “AMP-Activated Protein Kinase Agonists Increase mRNA Content of the Muscle-Specific Ubiquitin Ligases MAFbx and MuRF1 in C2C12 Cells,” American Journal of Physiology. Endocrinology and Metabolism 292, no. 6 (2007): E1555–E1567.

[13] A. L. Carey, G. R. Steinberg, S. L. Macaulay, et al., “Interleukin-6 Increases Insulin-Stimulated Glucose Disposal in Humans and Glucose Uptake and Fatty Acid Oxidation in Vitro via AMP-Activated Protein Kinase,” Diabetes 55, no. 10 (2006): 2688–2697.

[14] M. J. Yoon, G. Y. Lee, J. J. Chung, Y. H. Ahn, S. H. Hong, and J. B. Kim, “Adiponectin Increases Fatty Acid Oxidation in Skeletal Muscle Cells by Sequential Activation of AMP-activated Protein Kinase, p38 Mitogen-Activated Protein Kinase, and Peroxisome Proliferator-Activated Receptor α,” Diabetes 55, no. 9 (2006): 2562–2570.

[15] V. Ljubicic, P. Miura, M. Burt, et al., “Chronic AMPK Activation Evokes the Slow, Oxidative Myogenic Program and Triggers Beneficial Adaptations in mdx Mouse Skeletal Muscle,” Human Molecular Genetics 20, no. 17 (2011): 3478–3493.

[16] S. Y. Won, J. J. Park, E. Y. Shin, and E. G. Kim, “PAK4 signaling in Health and Disease: Defining the PAK4-CREB Axis,” Experimental & Molecular Medicine 51, no. 2 (2019): 1–9.

[17] H. C. Yu, B. H. Chung, Y. Kim, et al., “p21-activated Kinase 4 and Ischemic Acute Kidney Injury in Mice and Humans,” Journal of the American Society of Nephrology 36, no. 7 (2025): 1264–1277.

[18] Y. Mao, C. Y. Han, L. Hao, et al., “p21-Activated Kinase 4 Inhibition Protects Against Liver Ischemia/Reperfusion Injury: Role of Nuclear Factor Erythroid 2-Related Factor 2 Phosphorylation,” Hepatology 76, no. 2 (2022): 345–356.

[19] M. Y. Shi, H. C. Yu, C. Y. Han, et al., “p21-Activated Kinase 4 Suppresses Fatty Acid β-Oxidation and Ketogenesis by Phosphorylating NCoR1,” Nature Communications 14, no. 1 (2023): 4987.

[20] H. C. Yu, Y. G. Jeon, A. Y. Na, et al., “p21-Activated Kinase 4 Counteracts PKA-Dependent Lipolysis by Phosphorylating FABP4 and HSL,” Nature Metabolism 6, no. 1 (2024): 94–112.

[21] H. C. Yu, S. H. Park, H. J. Jo, et al., “PAK4 Phosphorylates Cyclin-Dependent Kinase 2 to Promote the G₁/S Transition During Adipogenesis,” Experimental & Molecular Medicine 57, no. 9 (2025): 2121–2132.

[22] D. Wu, H. C. Yu, H. N. Cha, et al., “PAK4 Phosphorylates and Inhibits AMPKα to Control Glucose Uptake,” Nature Communications 15, no. 1 (2024): 6858.

[23] Y. Mao, C. Y. Han, L. Hao, I. H. Bang, E. J. Bae, and B. H. Park, “p21-Activated Kinase 4 Phosphorylates Peroxisome Proliferator-Activated Receptor γ and Suppresses Skeletal Muscle Regeneration,” Journal of Cachexia, Sarcopenia and Muscle 12, no. 6 (2021): 1776–1788.

[24] S. C. Bodine, E. Latres, S. Baumhueter, et al., “Identification of Ubiquitin Ligases Required for Skeletal Muscle Atrophy,” Science 294 (2001): 1704–1708.

[25] G. Favaro, V. Romanello, T. Varanita, et al., “DRP1-Mediated Mitochondrial Shape Controls Calcium Homeostasis and Muscle Mass,” Nature Communications 10 (2019): 2576.

[26] P. Bonaldo and M. Sandri, “Cellular and Molecular Mechanisms of Muscle Atrophy,” Disease Models & Mechanisms 6 (2013): 25–39.

[27] S. A. Hawley, F. A. Ross, G. J. Gowans, P. Tibarewal, N. R. Leslie, and D. G. Hardie, “Phosphorylation by Akt Within the ST Loop of AMPK-α1 Down-Regulates Its Activation in Tumour Cells,” Biochemical Journal 459 (2014): 275–287.

[28] S. S. Wing and A. L. Goldberg, “Glucocorticoids Activate the ATP-Ubiquitin-Dependent Proteolytic System in Skeletal Muscle During Fasting,” American Journal of Physiology 264 (1993): E668–E676.

[29] Z. Hu, H. Wang, I. H. Lee, J. Du, and W. E. Mitch, “Endogenous Glucocorticoids and Impaired Insulin Signaling Are Both Required to Stimulate Muscle Wasting Under Pathophysiological Conditions in Mice,” Journal of Clinical Investigation 119, no. 10 (2009): 3059–3069.

[30] E. Castillero, N. Alamdari, S. H. Lecker, and P. O. Hasselgren, “Suppression of Atrogin-1 and MuRF1 Prevents Dexamethasone-Induced Atrophy of Cultured Myotubes,” Metabolism 62, no. 10 (2013): 1495–1502.

[31] H. Gilson, O. Schakman, L. Combaret, et al., “Myostatin Gene Deletion Prevents Glucocorticoid-Induced Muscle Atrophy,” Endocrinology 148, no. 1 (2007): 452–460.

[32] O. J. Shah, S. R. Kimball, and L. S. Jefferson, “Acute Attenuation of Translation Initiation and Protein Synthesis by Glucocorticoids in Skeletal Muscle,” American Journal of Physiology. Endocrinology and Metabolism 278, no. 1 (2000): E76–E82.

[33] T. Debevec, B. Ganse, U. Mittag, O. Eiken, I. B. Mekjavic, and J. Rittweger, “Hypoxia Aggravates Inactivity-Related Muscle Wasting,” Frontiers in Physiology 9 (2018): 494.

[34] M. J. Kang, J. W. Moon, J. O. Lee, et al., “Metformin Induces Muscle Atrophy by Transcriptional Regulation of Myostatin via HDAC6 and FoxO3a,” Journal of Cachexia, Sarcopenia and Muscle 13, no. 1 (2022): 605–620.

[35] E. A. de Lima, L. G. O. de Sousa, A. A. de S Teixeira, A. G. Marshall, N. E. Zanchi, and J. C. R. Neto, “Aerobic Exercise, but Not Metformin, Prevents Reduction of Muscular Performance by AMPK Activation in Mice on Doxorubicin Chemotherapy,” Journal of Cellular Physiology 233, no. 12 (2018): 9652–9662.

[36] J. J. Petrocelli, J. Liu, E. M. Yee, et al., “Skeletal Muscle-specific Inducible AMPKα1/α2 Knockout Mice Develop Muscle Weakness, Glycogen Depletion, and Fibrosis That Persists During Disuse Atrophy,” American Journal of Physiology. Endocrinology and Metabolism 326, no. 1 (2024): E50–E60.

[37] Y. Guo, J. Meng, Y. Tang, et al., “AMP-Activated Kinase α2 Deficiency Protects Mice From Denervation-Induced Skeletal Muscle Atrophy,” Archives of Biochemistry and Biophysics 600 (2016): 56–60.

[38] Y. Zhou, T. Lei, Z. Tang, et al., “Increased Phosphorylation of AMPKα1 S485 in Colorectal Cancer and Identification of PKCα as a Responsible Kinase,” Cancer Letters 611 (2024): 217418.

[39] P. Jiang, L. Ren, L. Zhi, et al., “Negative Regulation of AMPK Signaling by High Glucose via E3 Ubiquitin Ligase MG53,” Molecular Cell 81 (2021): 629–637.

[40] Z. Wu, P. Puigserver, U. Andersson, et al., “Mechanisms Controlling Mitochondrial Biogenesis and Respiration Through the Thermogenic Coactivator PGC-1,” Cell 98, no. 1 (1999): 115–124.

[41] J. Lin, H. Wu, P. T. Tarr, et al., “Transcriptional co-Activator PGC-1α Drives the Formation of Slow-Twitch Muscle Fibres,” Nature 418 (2002): 797–801.

[42] M. Sandri, J. Lin, C. Handschin, et al., “PGC-1α Protects Skeletal Muscle From Atrophy by Suppressing FoxO3 Action and Atrophy-Specific Gene Transcription,” PNAS 103 (2006): 16260–16265.

[43] D. Yeo, C. Kang, M. C. Gomez-Cabrera, J. Vina, and L. L. Ji, “Intensified Mitophagy in Skeletal Muscle With Aging Is Downregulated by PGC-1α Overexpression in Vivo,” Free Radical Biology and Medicine 130 (2019): 361–368.

[44] C. Zechner, L. Lai, J. F. Zechner, et al., “Total Skeletal Muscle PGC-1 Deficiency Uncouples Mitochondrial Derangements From fiber Type Determination and Insulin Sensitivity,” Cell Metabolism 12 (2010): 633–642.

[45] D. M. Thomson, “The Role of AMPK in the Regulation of Skeletal Muscle Size, Hypertrophy, and Regeneration,” International Journal of Molecular Sciences 19, no. 10 (2018): 3125.

[46] K. Nakashima and Y. Yakabe, “AMPK Activation Stimulates Myofibrillar Protein Degradation and Expression of Atrophy-Related Ubiquitin Ligases by Increasing FOXO Transcription Factors in C2C12 Myotubes,” Bioscience, Biotechnology, and Biochemistry 71, no. 7 (2007): 1650–1656.

[47] A. M. Owen and C. S. Fry, “Decoding the Decline: Unveiling Drivers of Sarcopenia,” Journal of Clinical Investigation 134, no. 16 (2024): e183302.

[48] H. L. Kerr, K. Krumm, B. Anderson, et al., “Mouse Sarcopenia Model Reveals Sex- and Age-Specific Differences in Phenotypic and Molecular Characteristics,” Journal of Clinical Investigation 134, no. 16 (2024): e172890.

[49] R. N. Baumgartner, K. M. Koehler, D. Gallagher, et al., “Epidemiology of Sarcopenia Among the Elderly in New Mexico,” American Journal of Epidemiology 147, no. 8 (1998): 755–763.

[50] L. K. Chen, J. Woo, P. Assantachai, et al., “Asian Working Group for Sarcopenia: 2019 Consensus Update on Sarcopenia Diagnosis and Treatment,” Journal of the American Medical Directors Association 21, no. 3 (2020): 300–307.

[51] X. Wei, H. Guo, G. Huang, et al., “SIRT1 alleviates Mitochondrial Fission and Necroptosis in Cerebral Ischemia/Reperfusion Injury via SIRT1-RIP1 Signaling Pathway,” MedComm (2020) 6, no. 3 (2025): e70118.

[52] H. Jiang, J. Zhang, D. Jia, et al., “Histidine Triad Nucleotide-Binding Protein 2 Attenuates Doxorubicin-induced Cardiotoxicity Through Restoring Lysosomal Function and Promoting Autophagy in Mice,” MedComm (2020) 6, no. 3 (2025): e70075.

RIGHTS & PERMISSIONS

2025 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.