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

Journal of Cachexia, Sarcopenia and Muscle

Pötsch Mareike S.³  Tschirner Anika³  Palus Sandra³  von Haehling Stephan³  Doehner Wolfram³  Beadle John¹  Coats Andrew J. S.²  Anker Stefan D.³ 

[1] PsiOxus Therapeutics, Oxford;Monash University, Melbourne;Applied Cachexia Research, Department of Cardiology, Charité Medical School, Berlin

关键词: Sarcopenia;    Anabolic catabolic transforming agent (ACTA);    Espindolol;    Muscle mass;    Fat mass;   

DOI  :  10.1007/s13539-013-0125-7

来源: Wiley

【 摘 要 】

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 NFκB, 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.

Electronic supplementary material

The online version of this article (doi:10.1007/s13539-013-0125-7) contains supplementary material.

【 授权许可】

CC BY-NC   
© 2014 The Authors. Published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders

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