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A Defective Extracellular Matrix/Kindlin-2/Actin/ERK Mechanosensing Pathway Affects Fibroblast-To-Myofibroblast Transition in the Old Male Heart

ABSTRACT: Heart failure represents a leading cause of mortality in the elderly population. Although aging features include diastolic dysfunction and interstitial fibrosis in both males and females, it becomes increasingly apparent that aged male and female hearts are phenotypically different. There were fundamental differences in extracellular matrix (ECM) composition and architecture and heart function indices at the baseline, which were further accentuated by Aicar treatment. By combining in vivo, ex vivo, and in vitro strategies, we demonstrated that there are sex-specific features that influence the response to pharmacological intervention in the aging mouse heart

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart

SUBMITTER: Antrix Jain

LAB HEAD: Katarzyna Cieslik

PROVIDER: PXD041660 | Pride | 2023-07-11

REPOSITORIES: Pride

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Project description:Normal aging can result in a decline of memory and muscle function. Exercise may prevent or delay these changes. However, aging associated frailty may preclude physical activity. AMP-activated protein kinase (AMPK) is a transcriptional regulator important for muscle physiology. In the present study we investigated effects of AMPK agonist 5-aminoimidazole-4-carboxamide riboside (AICAR) on memory and motor function in young (2-month-old), aged (23-month-old) C57Bl/6 mice, and transgenic mice with muscle-specific mutated AMPK alpha-subunit (AMPK-DN). Mice were injected with AICAR (500 mg/kg) for 3 to 14 days and tested in the Morris water maze, rotarod and open field. Improved water maze performance and motor function was observed, albeit at longer duration of administration, in aged (14 days AICAR) than young (3 days AICAR) mice. In the AMPKDN mice, the compound did not enhance behavior, providing support for a muscle mediated mechanism. In addition, microarray analysis of muscle and hippocampal tissue derived from aged mice treated with AICAR revealed changes in gene expression in both tissues, which correlated with behavioral effects in a dose-dependent manner. Pronounced up-regulation of mitochondrial genes in muscle was observed. In the hippocampus genes relevant to neuronal development and plasticity were enriched. Altogether, endurance related factors may mediate both muscle and brain health in aging, and could play a role in new therapeutic interventions. Key words: Skeletal Muscle, Brain, Exercise, AMPK, Learning and Memory, Morris water maze 23-month old female C57BL/6J mice (Jackson Laboratory, Bar Harbor, ME) were housed under standard conditions, 3 mice per cage, with food and water ad libitum. Mice were injected intraperitoneally with 5-Aminoimidazole-4-carboxamide-1-a-D-ribofuranoside (AICAR, Toronto Research Chemicals Inc., Canada) dissolved in saline, 500 mg/kg/day for 3 (ACR3), 7 (ACR7) or 14 (ACR14) days or saline vehicle, for 3 (CTR) days. Thirty-three days after the final injection animals were deeply anesthetized with isofluorane and perfused transcardially with 0.9% NaCl solution. The gastrocnemius muscle and Hippocampus were quickly removed, frozen on dry ice and stored at M-bM-^HM-^R80 M-BM-0C for RNA isolation and microarray analysis.

Dataset Information

A Defective Extracellular Matrix/Kindlin-2/Actin/ERK Mechanosensing Pathway Affects Fibroblast-To-Myofibroblast Transition in the Old Male Heart

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