The potential and the pitfalls of β-adrenoceptor agonists for the management of skeletal muscle wasting

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The β-adrenergic signaling pathway represents a novel therapeutic target for skeletal muscle wasting and weakness due to its role in the mechanisms controlling protein synthesis and degradation and in modulating fiber type. Stimulation of the pathway with β-adrenoceptor agonists (β-agonists) has therapeutic potential for muscle wasting disorders including: sarcopenia, cancer cachexia, disuse and inactivity, unloading or microgravity, sepsis and other metabolic disorders, denervation, burns, HIV-AIDS, chronic kidney or heart failure, and neuromuscular diseases. However, there are also pitfalls associated with β-agonist administration and clinical applications have so far been limited, largely because of cardiovascular side effects. In rats and mice, newer generation β-agonists (such as formoterol) can elicit an anabolic response in skeletal muscle even at very low doses, with reduced effects on the heart and cardiovascular system compared with older generation β-agonists (such as fenoterol and clenbuterol). However, the potentially deleterious cardiovascular side effects of β-agonists have not been obviated completely and so it is important to refine their development and therapeutic approach in order to overcome these obstacles. This review describes the therapeutic potential of stimulating the β-adrenergic signaling pathway with β-agonists, highlighting the beneficial effects on skeletal muscle structure and function and identifying some of the pitfalls associated with short- and long-term β-agonist administration. The review also identifies some important, but as yet unanswered questions, regarding the importance of β-adrenoceptor signaling in muscle health and disease and the strategies needed to improve the efficacy and safety of β-agonists for muscle wasting disorders.

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