MicroRNA regulators of cholinergic signaling link neuromuscular, cardiac and metabolic systems

Abstract

The neurotransmitter acetylcholine (ACh) notably regulates many brain and bodily functions, including metabolic as well as heart and muscle activities. Concordantly, acquired changes in ACh signaling lead to significant and widespread systemic effects. Those can be observed both when ACh signaling fails, as in the motor neuron disease amyotrophic lateral sclerosis (ALS) and when it over-reacts, as in the hyper-cholinergic excitation following organophosphate poisoning. To explore the corresponding molecular mechanisms, we focused on regulation of ACh signaling by microRNAs (miRs). Current research implicates miRs as post-transcriptional modulators of gene expression, playing pivotal, rapid and interactive roles across various systems. To interrogate the systemic role of ACh-regulating miRs (CholinomiRs), we sought evidence for CholinomiRs with dual or triple roles in neuromuscular junctions (NMJ), heart development and functioning, and/ or metabolic systems. Here, we report key links between CholinomiRs with known cardiac and metabolic roles, including the nicotinic acetylcholine receptor-targeted miR-1 and the acetylcholinesterase-targeted miR-132, and NMJ-related metabolic regulating miRs such as the histone deacetylase 4-targeted miR-206. Taken together, this information indicates a bridging role for CholinomiRs that may be relevant both for NMJ degeneration and the metabolic changes observed in ALS patients, and for the cardiac irregularities and NMJ degeneration reported following organophosphate poisoning. Uncovering the potentially causal involvement of CholinomiRs in balancing neuromuscular, cardiac and metabolic functions might improve our understanding of the inter-tissue communication and the processes of reaching homeostatic states which are essential for balancing between seemingly separate body systems, allowing a more encompassing look on disorders involving impaired cholinergic signaling.