Transcriptomic Mechanisms in Post-mitotic and Excitable Cells in Inter-Organ Communication
by Verena Gisa
Date of Examination:2025-05-22
Date of issue:2025-12-04
Advisor:Prof. Dr. André Fischer
Referee:Prof. Dr. André Fischer
Referee:Prof. Dr. Wolfram-Hubertus Zimmermann
Persistent Address:
http://dx.doi.org/10.53846/goediss-11618
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Abstract
English
The human body functions as an integrated network where organs communicate through complex molecular signals rather than as isolated systems. This inter-organ communication occurs through various mediators including proteins, metabolites, hormones, extracellular vesicles, and non-coding RNAs. Disruptions in these communication pathways contribute to the development of comorbidities, while enhancement of these pathways through interventions like exercise promotes systemic resilience. The heart-brain and muscle-brain axes represent critical examples of such inter-organ communication, with mounting evidence demonstrating how cardiac dysfunction impacts cognitive health and how skeletal muscle activity influences brain function through circulating factors. Cardiovascular disease remains the leading cause of global mortality, accounting for approximately 34% of deaths worldwide. Heart failure patients exhibit 1.5 to 1.8 times higher risk of developing cognitive impairment and dementia, highlighting the existence of bidirectional communication pathways between heart and brain. This relationship manifests through multiple mechanisms including reduced cerebral perfusion, neuroinflammation, and systemic metabolic dysregulation. Similarly, physical exercise consistently improves cognitive function and decreases neurodegeneration risk through muscle-derived factors that cross the blood-brain barrier to enhance neuroplasticity and glial support functions. Non-coding RNAs have emerged as critical regulators of these inter-organ communication pathways, functioning both as messengers and modulators of downstream effects. MicroRNAs (miRNAs), small non-coding RNAs typically 20-25 nucleotides in length, regulate gene expression post-transcriptionally by binding to complementary sequences in target mRNAs. Long non-coding RNAs (lncRNAs), defined as transcripts exceeding 200 nucleotides without protein-coding potential, exhibit diverse regulatory functions including transcriptional regulation, chromatin remodeling, and protein complex scaffolding. Both classes of non- coding RNAs display tissue and cell-type specificity, making them attractive therapeutic targets for modulating pathological processes in cardiac and neurological diseases while minimizing off-target effects. In the first project the aim was to investigate the molecular basis of exercise-induced brain benefits. Therefore, I developed an in vitro model using electrically stimulated muscle cells to examine how muscle-derived factors directly influence brain cell function. The secretome from stimulated muscle cells significantly enhanced neuronal activity, increased mushroom spine density, and upregulated genes associated with synaptic plasticity in primary neurons. In primary astrocytes, muscle-derived factors enhanced supportive functions, particularly glutamate uptake and phagocytic activity, despite minimal transcriptomic changes. Interestingly, microglia showed limited responses to the muscle secretome, suggesting cell type-specific mechanisms in the brain's response to peripheral signals. These findings demonstrate that muscle-derived factors alone, independent of systemic adaptations like increased cerebral blood flow, can directly enhance brain cell function. In the second project we investigated cognitive impairment in the CaMKIIδC transgenic mouse model of heart failure. While 3-month-old transgenic mice exhibited significant memory impairments and extensive hippocampal transcriptional dysregulation, these deficits were largely resolved by 6 months of age. Through RNA sequencing and small RNA sequencing, we discovered a compensatory network of 27 microRNAs that reinstated normal expression of genes critical for hippocampal function. This compensatory miRNA signature, centered around miR-181a-5p as a hub regulator and including members of the let-7 and miR-29 families, targeted 73% of reinstated transcripts, demonstrating the powerful role of miRNAs in buffering transcriptional fluctuations during disease progression. These findings challenge linear models of heart failure-induced cognitive decline and reveal endogenous resilience mechanisms that may represent novel therapeutic targets. In my last project I characterized a cardiomyocyte-specific long non-coding RNA (CRMA) with complex roles in cardiac health and disease. CRMA is consistently deregulated across various cardiac pathologies, including dilated cardiomyopathy, ischemic cardiomyopathy, and heart failure with reduced ejection fraction. Using iPSC-derived cardiomyocytes, I demonstrated that CRMA knockdown produced paradoxical effects: downregulating hypertrophic marker genes while simultaneously disrupting pathways essential for cardiomyocyte structural integrity. In an endothelin-1- induced hypertrophy model, CRMA depletion attenuated hypertrophic responses and selectively restored potassium currents without affecting sodium or calcium homeostasis. These findings suggest CRMA functions both in maintaining normal cardiomyocyte structure and in promoting pathological hypertrophic responses, highlighting the complex roles of lncRNAs in cardiac physiology and disease. Collectively, these projects establish non-coding RNAs as critical mediators of inter-organ communication, functioning both as messengers between distant tissues and as regulators that coordinate complex cellular responses. The identification of a compensatory miRNA network in heart failure, the characterization of CRMA's dual role in cardiac health and disease, and the demonstration that muscle-derived factors directly modulate neuronal and astrocytic function advance our understanding of how organs communicate and coordinate responses to physiological and pathological stimuli. This work provides insights into potential therapeutic strategies targeting inter-organ communication pathways, such as modulating specific miRNAs to enhance cognitive resilience in heart failure patients, targeting CRMA to attenuate pathological cardiac hypertrophy, and harnessing muscle-derived factors to promote brain health in individuals with limited exercise capacity.
Keywords: Inter-Organ Communication; Heart; Brain; non-coding RNAs; microRNAs; lncRNA; Cardiac Disease; Transcriptomics
