title: The anabolic catabolic transforming agent (ACTA) espindolol increases muscle mass and decreases fat mass in old rats.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Applied Cachexia Research, Department of Cardiology, Charité Medical School, Berlin, Germany.
authors.forename: Mareike S
authors.initials: MS
authors.lastname: Pötsch
authors.forename: Anika
authors.initials: A
authors.lastname: Tschirner
authors.forename: Sandra
authors.initials: S
authors.lastname: Palus
authors.forename: Stephan
authors.initials: S
authors.lastname: von Haehling
authors.forename: Wolfram
authors.initials: W
authors.lastname: Doehner
authors.forename: John
authors.initials: J
authors.lastname: Beadle
authors.forename: Andrew J S
authors.initials: AJ
authors.lastname: Coats
authors.forename: Stefan D
authors.initials: SD
authors.lastname: Anker
authors.forename: Jochen
authors.initials: J
authors.lastname: Springer