TY - JOUR
T1 - Interleukin-6 Drives Mitochondrial Dysregulation and Accelerates Physical Decline
T2 - Insights From an Inducible Humanized IL-6 Knock-In Mouse Model
AU - Nidadavolu, Lolita S.
AU - Cosarderelioglu, Caglar
AU - Gomez, Alessandra Merino
AU - Wu, Yuqiong
AU - Bopp, Taylor
AU - Zhang, Cissy
AU - Nguyen, Tu
AU - Marx-Rattner, Ruth
AU - Yang, Huanle
AU - Antonescu, Corina
AU - Florea, Liliana
AU - Talbot, Conover C.
AU - Smith, Barbara
AU - Foster, D. Brian
AU - Fairman, Jennifer E.
AU - Yenokyan, Gayane
AU - Chung, Tae
AU - Le, Anne
AU - Walston, Jeremy D.
AU - Abadir, Peter M.
N1 - Publisher Copyright:
© The Author(s) 2023.
PY - 2023/10/1
Y1 - 2023/10/1
N2 - Chronic activation of inflammatory pathways (CI) and mitochondrial dysfunction are independently linked to age-related functional decline and early mortality. Interleukin 6 (IL-6) is among the most consistently elevated chronic activation of inflammatory pathways markers, but whether IL-6 plays a causative role in this mitochondrial dysfunction and physical deterioration remains unclear. To characterize the role of IL-6 in age-related mitochondrial dysregulation and physical decline, we have developed an inducible human IL-6 (hIL-6) knock-in mouse (TetO-hIL-6mitoQC) that also contains a mitochondrial-quality control reporter. Six weeks of hIL-6 induction resulted in upregulation of proinflammatory markers, cell proliferation and metabolic pathways, and dysregulated energy utilization. Decreased grip strength, increased falls off the treadmill, and increased frailty index were also observed. Further characterization of skeletal muscles postinduction revealed an increase in mitophagy, downregulation of mitochondrial biogenesis genes, and an overall decrease in total mitochondrial numbers. This study highlights the contribution of IL-6 to mitochondrial dysregulation and supports a causal role of hIL-6 in physical decline and frailty.
AB - Chronic activation of inflammatory pathways (CI) and mitochondrial dysfunction are independently linked to age-related functional decline and early mortality. Interleukin 6 (IL-6) is among the most consistently elevated chronic activation of inflammatory pathways markers, but whether IL-6 plays a causative role in this mitochondrial dysfunction and physical deterioration remains unclear. To characterize the role of IL-6 in age-related mitochondrial dysregulation and physical decline, we have developed an inducible human IL-6 (hIL-6) knock-in mouse (TetO-hIL-6mitoQC) that also contains a mitochondrial-quality control reporter. Six weeks of hIL-6 induction resulted in upregulation of proinflammatory markers, cell proliferation and metabolic pathways, and dysregulated energy utilization. Decreased grip strength, increased falls off the treadmill, and increased frailty index were also observed. Further characterization of skeletal muscles postinduction revealed an increase in mitophagy, downregulation of mitochondrial biogenesis genes, and an overall decrease in total mitochondrial numbers. This study highlights the contribution of IL-6 to mitochondrial dysregulation and supports a causal role of hIL-6 in physical decline and frailty.
KW - Inflammation
KW - Mitochondria dysregulation
KW - Physical decline
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U2 - 10.1093/gerona/glad147
DO - 10.1093/gerona/glad147
M3 - Article
C2 - 37310873
AN - SCOPUS:85173584902
SN - 1079-5006
VL - 78
SP - 1740
EP - 1752
JO - Journals of Gerontology - Series A Biological Sciences and Medical Sciences
JF - Journals of Gerontology - Series A Biological Sciences and Medical Sciences
IS - 10
ER -