Tuning the Consonance of Microscopic Neuro-Cardiac Interactions Allows the Heart Beats to Play Countless Genres

Abstract

Different from skeletal muscle, the heart autonomously generates rhythmic contraction independently from neuronal inputs. However, speed and strength of the heartbeats are continuously modulated by environmental, physical or emotional inputs, delivered by cardiac innervating sympathetic neurons, which tune cardiomyocyte (CM) function, through activation of β-adrenoceptors (β-ARs). Given the centrality of such mechanism in heart regulation, β-AR signaling has been subject of intense research, which has reconciled the molecular details of the transduction pathway and the fine architecture of cAMP signaling in subcellular nanodomains, with its final effects on CM function. The importance of mechanisms keeping the elements of β-AR/cAMP signaling in good order emerges in pathology, when the loss of proper organization of the transduction pathway leads to detuned β-AR/cAMP signaling, with detrimental consequences on CM function. Despite the compelling advancements in decoding cardiac β-AR/cAMP signaling, most discoveries on the subject were obtained in isolated cells, somehow neglecting that complexity may encompass the means in which receptors are activated in the intact heart. Here, we outline a set of data indicating that, in the context of the whole myocardium, the heart orchestra (CMs) is directed by a closely interacting and continuously attentive conductor, represented by SNs. After a roundup of literature on CM cAMP regulation, we focus on the unexpected complexity and roles of cardiac sympathetic innervation, and present the recently discovered Neuro-Cardiac Junction, as the election site of “SN-CM” interaction. We further discuss how neuro-cardiac communication is based on the combination of extra- and intra-cellular signaling micro/nano-domains, implicating neuronal neurotransmitter exocytosis, β-ARs and elements of cAMP homeostasis in CMs, and speculate on how their dysregulation may reflect on dysfunctional neurogenic control of the heart in pathology.

Sympathetic neuropathology is revealed in muscles affected by amyotrophic lateral sclerosis

“…In the case of neuro-muscular interactions, autonomic neurons, and in particular SNs, have long been shown to innervate both the working myocardium and skeletal muscles (Straka et al, 2018;Pianca et al, 2019;Di Bona et al, 2020). In the heart, the effects of neurogenic regulation are undoubted and manifest with the perceptible increase in rate and contraction force, during physiological (e.g., emotions and exercise) or pathological (e.g., pressure overload and hypovolemia) stresses (Zaglia and Mongillo, 2017;Franzoso et al, 2022). Despite the effects of sympathetic activation on the cardiovascular system reflecting on important clinical consequences (i.e., syncope and arrhythmias) and yielding several methods to infer neuronal function (e.g., blood pressure, heart rate variability, cardiovascular effect of postural changes, scintigraphy, and PET), the characteristics of myocardial sympathetic innervation were only recently appreciated upon investigation of cardiac neurons with enhanced tools and refined techniques (for reviews on the topic, see Di Bona et al, 2020;Scalco et al, 2021).…”

“…In the first place, physical-chemical factors are associated with the tissue, in which preparation may affect SN cytoarchitecture. SN processes are made of small-sized unmyelinated fibers (Zaglia and Mongillo, 2017;Franzoso et al, 2022), and the absence of a lipid layer is expected to increase vulnerability to the effects of freezing, e.g., ice crystal formation, which would only minimally impinge on MN axons or the firm structure of muscle cytoskeleton. Notably, in muscles processed with conventional cryopreservation, residual SNs appear in proximity to blood vessels, which may be explained by uneven freezing-dependent deterioration on Frontiers in Physiology frontiersin.org…”

Healthy cardiac myocytes can decrease sympathetic hyperexcitability in the early stages of hypertension

“…Combined with a slow re-uptake of norepinephrine by the noradrenaline-transporter (NET) ( Shanks et al, 2013 ), the post-ganglionic pre-synaptic neuron appears to be a powerful driver of myocyte function. Moreover, it is well established in the SHR that a diseased Ca 2+ phenotype also resides in the myocytes ( Heaton et al, 2006 ), where recent evidence suggests that retrograde signaling from the myocyte itself might modulate synaptic plasticity ( Habecker et al, 2016 ; Prando et al, 2018 ; Franzoso et al, 2022 ).…”

Neurotoxic Effect of Doxorubicin Treatment on Cardiac Sympathetic Neurons

“…At the contact site, a tight intercellular interaction occurs between the neuron and the targeted CM, which underlays both anterograde (SN-to-CM) and retrograde (CM–SN) communication. Through the former, SNs stimulate the heart via noradrenaline which, by activating β-adrenoceptors (β-ARs), enhances heart rate and contractility during stresses [ 25 , 39 , 41 ], and modulates CM size and electrophysiology, by regulating proteostasis [ 41 , 42 , 43 ]. In parallel, reverse cardio-neuronal signaling, enacted through nerve growth factor (NGF), provides the continuing trophic input that is required to maintain the functioning and correctly patterned innervation in the developed heart [ 40 ].…”