The role of beta-adrenoceptor signaling in skeletal muscle: therapeutic implications for muscle wasting disorders

PURPOSE OF REVIEW: The beta-adrenergic signaling pathway represents a novel therapeutic target for skeletal muscle wasting disorders due to its roles in regulating protein synthesis and degradation. beta-Adrenoceptor agonists (beta-agonists) have therapeutic potential for attenuating muscle wasting associated with sarcopenia (age-related muscle wasting), cancer cachexia, sepsis, disuse, burns, HIV-AIDS, chronic kidney or heart failure, and neuromuscular diseases such as the muscular dystrophies. This review describes the role of beta-adrenergic signaling in the mechanisms controlling muscle wasting due to its effects on protein synthesis, protein degradation, and muscle fiber phenotype. RECENT FINDINGS: Stimulation of the beta-adrenergic signaling pathway with beta-agonists has therapeutic potential for muscle wasting since administration can elicit an anabolic response in skeletal muscle. As a consequence of their potent muscle anabolic actions, the effects of beta-agonist administration have been examined in several animal models and human conditions of muscle wasting in the hope of discovering a new therapeutic. The repartitioning characteristics of beta-agonists (increasing muscle mass and decreasing fat mass) have also made them attractive anabolic agents for use in livestock and by some athletes. However, potentially deleterious cardiovascular side-effects of beta-agonists have been identified and these will need to be obviated in order for the therapeutic potential of beta-agonists to be realized. SUMMARY: Multiple studies have identified anticachectic effects of beta-agonists and their therapeutic potential for pathologic states when muscle protein hypercatabolism is indicated. Future studies examining beta-agonist administration for muscle wasting conditions need to separate beneficial effects on skeletal muscle from potentially deleterious effects on the heart and cardiovascular system

The methyltransferase SMYD3 mediates the recruitment of transcriptional cofactors at the myostatin and c-Met genes and regulates skeletal muscle atrophy

Elucidating the epigenetic mechanisms underlying muscle mass determination and skeletal muscle wasting holds the potential of identifying molecular pathways that constitute possible drug targets. Here, we report that the methyltransferase SMYD3 modulates myostatin and c-Met transcription in primary skeletal muscle cells and C2C12 myogenic cells. SMYD3 targets the myostatin and c-Met genes and participates in the recruitment of the bromodomain protein BRD4 to their regulatory regions through protein-protein interaction. By recruiting BRD4, SMYD3 favors chromatin engagement of the pause-release factor p-TEFb (positive transcription elongation factor) and elongation of Ser2-phosphorylated RNA polymerase II (PolIISer2P). Reducing SMYD3 decreases myostatin and c-Met transcription, thus protecting from glucocorticoid-induced myotube atrophy. Supporting functional relevance of the SMYD3/BRD4 interaction, BRD4 pharmacological blockade by the small molecule JQ1 prevents dexamethasone-induced myostatin and atrogene up-regulation and spares myotube atrophy. Importantly, in a mouse model of dexamethasone-induced skeletal muscle atrophy, SMYD3 depletion prevents muscle loss and fiber size decrease. These findings reveal a mechanistic link between SMYD3/BRD4-dependent transcriptional regulation, muscle mass determination, and skeletal muscle atrophy and further encourage testing of small molecules targeting specific epigenetic regulators in animal models of muscle wasting