The anabolic catabolic transforming agent (ACTA) espindolol increases muscle mass and decreases fat mass in old rats

Mareike S Potsch, Anika Tschirner, Sandra Palus, Stephan von Haehling, Wolfram Doehner, John Beadle, Andrew Justin Stewart Coats, Stefan D Anker, Jochen Springer

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    Abstract

    Background: Sarcopenia, the age-related, progressive loss of skeletal muscle mass, strength, and function, is a considerable socioeconomic burden by increasing risks of falls, fractures, and frailty. Moreover, sarcopenic patients are often obese and therapeutic options are very limited. Methods: Here, we assessed the efficacy of espindolol on muscle mass in 19-month-old male Wistar Han rats (weight, 555 ? 18 g), including safety issues. Rats were randomized to treatment with 3 mg/kg/day espindolol (n = 8) or placebo (n = 14) for 31 days. Results: Placebo-treated rats progressively lost body weight (-15.5 ? 7.2 g), lean mass (-1.5 ? 4.2 g), and fat mass (-15.6 ? 2.7 g), while espindolol treatment increased body weight (+8.0 ? 6.1 g, p <0.05), particularly lean mass (+43.4 ? 3.5 g, p <0.001), and reduced fat mass further (-38.6 ? 3.4 g, p <0.001). Anabolic/catabolic signaling was assessed in gastrocnemius muscle. Espindolol decreased proteasome and caspase-3 proteolytic activities by approximately 50 (all p <0.05). Western blotting showed a reduced expression of key catabolic regulators, including NF?B, MuRF1, and LC-3 (all p <0.01). The 50- and 26-kDa forms of myostatin were downregulated fivefold and 20-fold, respectively (both p <0.001). Moreover, 4E-BP-1 was reduced fivefold (p <0.01), while phospho-PI3K was upregulated fivefold (p <0.001), although Akt expression and phosphorylation were lower compared to placebo (all p <0.05). No regulation of p38 and expression of ERK1/2 were observed, while phosphorylation of p38 was reduced (-54 , p <0.001) and ERK1/2 was increased (115 and 83 , respectively, both p <0.01). Espindolol did not affect cardiac function (echocardiography) or clinical plasma parameters. Conclusion: Espindolol reversed the effects of aging/sarcopenia, particularly loss of muscle mass and increased fat mass. Thus, espindolol is an attractive candidate drug for the treatment of sarcopenia patients
    Original languageEnglish
    Pages (from-to)149 - 158
    Number of pages10
    JournalJournal of Cachexia, Sarcopenia and Muscle
    Volume5
    Issue number2
    DOIs
    Publication statusPublished - 2014

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