Browsing by Subject "Carvedilol"

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    ItemOpen Access
    The β-arrestin-biased β-adrenergic receptor blocker carvedilol enhances skeletal muscle contractility.
    (Proceedings of the National Academy of Sciences of the United States of America, 2020-06) Kim, Jihee; Grotegut, Chad A; Wisler, James W; Mao, Lan; Rosenberg, Paul B; Rockman, Howard A; Lefkowitz, Robert J
    A decrease in skeletal muscle strength and functional exercise capacity due to aging, frailty, and muscle wasting poses major unmet clinical needs. These conditions are associated with numerous adverse clinical outcomes including falls, fractures, and increased hospitalization. Clenbuterol, a β2-adrenergic receptor (β2AR) agonist enhances skeletal muscle strength and hypertrophy; however, its clinical utility is limited by side effects such as cardiac arrhythmias mediated by G protein signaling. We recently reported that clenbuterol-induced increases in contractility and skeletal muscle hypertrophy were lost in β-arrestin 1 knockout mice, implying that arrestins, multifunctional adapter and signaling proteins, play a vital role in mediating the skeletal muscle effects of β2AR agonists. Carvedilol, classically defined as a βAR antagonist, is widely used for the treatment of chronic systolic heart failure and hypertension, and has been demonstrated to function as a β-arrestin-biased ligand for the β2AR, stimulating β-arrestin-dependent but not G protein-dependent signaling. In this study, we investigated whether treatment with carvedilol could enhance skeletal muscle strength via β-arrestin-dependent pathways. In a murine model, we demonstrate chronic treatment with carvedilol, but not other β-blockers, indeed enhances contractile force in skeletal muscle and this is mediated by β-arrestin 1. Interestingly, carvedilol enhanced skeletal muscle contractility despite a lack of effect on skeletal muscle hypertrophy. Our findings suggest a potential unique clinical role of carvedilol to stimulate skeletal muscle contractility while avoiding the adverse effects with βAR agonists. This distinctive signaling profile could present an innovative approach to treating sarcopenia, frailty, and secondary muscle wasting.
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    β-arrestin1-biased β1-adrenergic receptor signaling regulates microRNA processing.
    (Circulation research, 2014-02) Kim, Il-Man; Wang, Yongchao; Park, Kyoung-Mi; Tang, Yaoping; Teoh, Jian-Peng; Vinson, Joseph; Traynham, Christopher J; Pironti, Gianluigi; Mao, Lan; Su, Huabo; Johnson, John A; Koch, Walter J; Rockman, Howard A

    Rationale

    MicroRNAs (miRs) are small, noncoding RNAs that function to post-transcriptionally regulate gene expression. First transcribed as long primary miR transcripts (pri-miRs), they are enzymatically processed in the nucleus by Drosha into hairpin intermediate miRs (pre-miRs) and further processed in the cytoplasm by Dicer into mature miRs where they regulate cellular processes after activation by a variety of signals such as those stimulated by β-adrenergic receptors (βARs). Initially discovered to desensitize βAR signaling, β-arrestins are now appreciated to transduce multiple effector pathways independent of G-protein-mediated second messenger accumulation, a concept known as biased signaling. We previously showed that the β-arrestin-biased βAR agonist, carvedilol, activates cellular pathways in the heart.

    Objective

    Here, we tested whether carvedilol could activate β-arrestin-mediated miR maturation, thereby providing a novel potential mechanism for its cardioprotective effects.

    Methods and results

    In human cells and mouse hearts, carvedilol upregulates a subset of mature and pre-miRs, but not their pri-miRs, in β1AR-, G-protein-coupled receptor kinase 5/6-, and β-arrestin1-dependent manner. Mechanistically, β-arrestin1 regulates miR processing by forming a nuclear complex with hnRNPA1 and Drosha on pri-miRs.

    Conclusions

    Our findings indicate a novel function for β1AR-mediated β-arrestin1 signaling activated by carvedilol in miR biogenesis, which may be linked, in part, to its mechanism for cell survival.