The role of interleukin-10 in mitigating endoplasmic reticulum stress in aged mice through exercise

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Marafon, Bruno Brieda ; Pinto, Ana Paula ; de Sousa Neto, Ivo Vieira ; da Luz, Caroline Mantovani ; Pauli, Jose Rodrigo ; Cintra, Dennys Esper ; Ropelle, Eduardo Rochete ; Simabuco, Fernando Moreira ; de Moura, Leandro Pereira ; de Freitas, Ellen Cristini ; Rivas, Donato Americo ; da Silva, Adelino Sanchez Ramos

• Document type: Journal article
• Source: AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM; v. 327, n. 3, p. 12-pg., 2024-09-01.

Abstract

Although unfolded protein response (UPR) is essential for cellular protection, its prolonged activation may induce apoptosis, compromising cellular longevity. The aging process increases the endoplasmic reticulum (ER) stress in skeletal muscle. However, whether combined exercise can prevent age-induced ER stress in skeletal muscle remains unknown. Evidence suggests that ER stress may increase inflammation by counteracting the positive effects of interleukin-10 (IL-10), whereas its administration in cells inhibits ER stress and apoptosis. This study verified the effects of aging and combined exercise on physical performance, ER stress markers, and inflammation in the quadriceps of mice. Moreover, we verified the effects of IL-10 on ER stress markers. C57BL/6 mice were distributed into young (Y, 6 mo old), old sedentary (OS, sedentary, 24 mo old), and old trained group (OT, submitted to short-term combined exercise, 24 mo old). To clarify the role of IL-10 in UPR pathways, knockout mice lacking IL-10 were used. The OS mice presented worse physical performance and higher ER stress-related proteins, such as C/EBP homologous protein (CHOP) and phospho-eukaryotic translation initiation factor 2 alpha (p-eIF2 alpha/eIF2 alpha). The exercise protocol increased muscle strength and IL-10 protein levels in OT while inducing the downregulation of CHOP protein levels compared with OS. Furthermore, mice lacking IL-10 increased BiP, CHOP, and p-eIF2 alpha/eIF2 alpha protein levels, indicating this cytokine can regulate the ER stress response in skeletal muscle. Bioinformatics analysis showed that endurance and resistance training downregulated DNA damage inducible transcript 3 (DDIT3) and XBP1 gene expression in the vastus lateralis of older people, reinforcing our findings. Thus, combined exercise is a potential therapeutic intervention for promoting adjustments in ER stress markers in aged skeletal muscle. (AU)

• FAPESP's process: 21/06291-3 - Multi-user Equipament approved in grant 2019/11820-5: ChemiDoc Imaging System and accessories
• Grantee: Adelino Sanchez Ramos da Silva
• Support Opportunities: Multi-user Equipment Program
• FAPESP's process: 21/08693-1 - Effect of global or conditional deletion (skeletal muscle) of the Nr1d1 gene on aging
• Grantee: Ana Paula Pinto
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 21/14233-3 - Effects of PGC-1alpha conditional deletion and exercise on mitochondrial biogenesis, autophagy and rev-erb-alpha pathways in mouse skeletal muscle: a proteomics approach
• Grantee: Ivo Vieira de Sousa Neto
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 19/11820-5 - Nr1d1 function on the aging-associated Sarcopenia
• Grantee: Adelino Sanchez Ramos da Silva
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 22/09100-7 - Role of rev-erb-alpha in aging-associated endoplasmic reticulum stress
• Grantee: Bruno Brieda Marafon
• Support Opportunities: Scholarships in Brazil - Doctorate