ABSTRACT
BACKGROUND: Cognitive impairment is a serious comorbidity in heart failure patients, but effective therapies are lacking. We investigated the mechanisms that alter hippocampal neurons following myocardial infarction (MI). METHODS: MI was induced in male C57Bl/6 mice by left anterior descending coronary artery ligation. We utilised standard procedures to measure cystic fibrosis transmembrane regulator (CFTR) protein levels, inflammatory mediator expression, neuronal structure, and hippocampal memory. Using in vitro and in vivo approaches, we assessed the role of neuroinflammation in hippocampal neuron degradation and the therapeutic potential of CFTR correction as an intervention. FINDINGS: Hippocampal dendrite length and spine density are reduced after MI, effects that associate with decreased neuronal CFTR expression and concomitant microglia activation and inflammatory cytokine expression. Conditioned medium from lipopolysaccharide-stimulated microglia (LCM) reduces neuronal cell CFTR protein expression and the mRNA expression of the synaptic regulator post-synaptic density protein 95 (PSD-95) in vitro. Blocking CFTR activity also down-regulates PSD-95 in neurons, indicating a relationship between CFTR expression and neuronal health. Pharmacologically correcting CFTR expression in vitro rescues the LCM-mediated down-regulation of PSD-95. In vivo, pharmacologically increasing hippocampal neuron CFTR expression improves MI-associated alterations in neuronal arborisation, spine density, and memory function, with a wide therapeutic time window. INTERPRETATION: Our results indicate that CFTR therapeutics improve inflammation-induced alterations in hippocampal neuronal structure and attenuate memory dysfunction following MI. FUNDING: Knut and Alice Wallenberg Foundation [F 2015/2112]; Swedish Research Council [VR; 2017-01243]; the German Research Foundation [DFG; ME 4667/2-1]; Hjärnfonden [FO2021-0112]; The Crafoord Foundation; Åke Wibergs Stiftelse [M19-0380], NMMP 2021 [V2021-2102]; the Albert Påhlsson Research Foundation; STINT [MG19-8469], Lund University; Canadian Institutes of Health Research [PJT-153269] and a Heart and Stroke Foundation of Ontario Mid-Career Investigator Award.
Subject(s)
Amnesia, Retrograde , Cystic Fibrosis Transmembrane Conductance Regulator , Myocardial Infarction , Animals , Male , Mice , Cystic Fibrosis Transmembrane Conductance Regulator/drug effects , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Lipopolysaccharides , Memory, Long-Term/physiology , Mice, Inbred C57BL , Myocardial Infarction/complications , Myocardial Infarction/drug therapy , Ontario , Amnesia, Retrograde/drug therapy , Amnesia, Retrograde/metabolism , Disks Large Homolog 4 Protein/genetics , Disks Large Homolog 4 Protein/metabolismABSTRACT
Aging is characterized by a progressive decline in tissue and organ function often linked to a reduced stem cell functionality, a cell population important for regeneration. Skeletal muscle mass and regenerative capacity decrease with advancing age. Muscle stem cells, also termed satellite cells, are a prerequisite for regeneration of skeletal muscle. Their functionality declines with increasing age, driven by intrinsic changes and changes in the stem cell niche. Here, we discuss the current understanding how muscle stem cells are affected during aging. The aging associated alterations include among others upregulation of developmental pathways in aged muscle stem cells and changes in the extracellular matrix.