Alterations of cAMP-dependent signaling in dystrophic skeletal muscle

Abstract

Autonomic regulation processes in striated muscles are largely mediated by cAMP/PKA-signaling. In order to achieve specificity of signaling its spatial-temporal compartmentation plays a critical role. We discuss here how specificity of cAMP/PKA-signaling can be achieved in skeletal muscle by spatio-temporal compartmentation. While a microdomain containing PKA type I in the region of the neuromuscular junction (NMJ) is important for postsynaptic, activity-dependent stabilization of the nicotinic acetylcholine receptor (AChR), PKA type I and II microdomains in the sarcomeric part of skeletal muscle are likely to play different roles, including the regulation of muscle homeostasis. These microdomains are due to specific A-kinase anchoring proteins, like rapsyn and myospryn. Importantly, recent evidence indicates that compartmentation of the cAMP/PKA-dependent signaling pathway and pharmacological activation of cAMP production are aberrant in different skeletal muscles disorders. Thus, we discuss here their potential as targets for palliative treatment of certain forms of dystrophy and myasthenia. Under physiological conditions, the neuropeptide, α-calcitonin-related peptide, as well as catecholamines are the most-mentioned natural triggers for activating cAMP/PKA signaling in skeletal muscle. While the precise domains and functions of these first messengers are still under investigation, agonists of β2-adrenoceptors clearly exhibit anabolic activity under normal conditions and reduce protein degradation during atrophic periods. Past and recent studies suggest direct sympathetic innervation of skeletal muscle fibers. In summary, the organization and roles of cAMP-dependent signaling in skeletal muscle are increasingly understood, revealing crucial functions in processes like nerve-muscle interaction and muscle trophicity.

The beta-adrenergic agonist salbutamol modulates neuromuscular junction formation in zebrafish models of human myasthenic syndromes

“…β agonist therapy may therefore also play a role in postsynaptic differentiation in mammals. Indeed, several lines of evidence point toward cAMP/PKA-dependent pathways involved in metabolic stabilization of AChRs ( 31–33 ).…”

Postnatal Development and Distribution of Sympathetic Innervation in Mouse Skeletal Muscle

“…In recent years, sympathicomimetic drugs, such as ephedrine or salbutamol, have proven to be rather effective in many CMS patients, but the underlying mechanisms of action have remained unclear [ 2 ]. A potential link of these clinical findings to NMJ biology has been the recent observation of extensive interaction between sympathetic neurons and NMJs [ 3 , 4 ]. Indeed, in adult mouse extensor digitorum longus and diaphragm muscles, sympathetic neurons were found to form ample networks between motor neurons, blood vessels, and muscle fibers [ 4 ].…”

Protein Kinase A Activation Enhances β-Catenin Transcriptional Activity through Nuclear Localization to PML Bodies

“…These signaling cascades play complex roles in differentiation, development, and tumorigenesis, where effects within a specific tissue or developmental stage are highly dependent on context. Proper regulation of these pathways is required for normal formation of both epithelial and mesenchymal tissue, such as bone and muscle [1] , [2] , [3] , [4] .…”