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

Abstract

BackgroundSarcopenia, 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.MethodsHere, 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.ResultsPlacebo-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.ConclusionEspindolol 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 materialThe online version of this article (doi:10.1007/s13539-013-0125-7) contains supplementary material.

Establishment and characterization of a novel murine model of pancreatic cancer cachexia

“…Many studies have examined the role of increased sympathetic outflow in cachexia as a means of energy loss. The relevance of this mechanism is underscored by the ameliorative effects on sarcopenia and cachexia observed with the anabolic catabolic transforming agent espindolol, which acts as a nonspecific beta‐1 and beta‐2 adrenergic receptor antagonist 50, 51. Sympathetic outflow increases can manifest as ‘browning’ of WAT or an increase of BAT activity through increased expression of genes such as Ucp1.…”

Pathogenesis and Management of Sarcopenia

“…(34) In aged animal models, MT-102 has shown to reverse sarcopenia. (35) Further studies of MT-102 as a treatment of sarcopenia are currently underway. Another clinical trial using intravenous BYM338 (bimagrumab) in patients with sarcopenia is currently enrolling subjects.…”

Skeletal muscle wasting in chronic heart failure

“…111 Human myocardium expressed myostatin in end-stage heart failure and the related signalling pathways in the myocardium seen to have a gender effect. 124 Importantly, espindolol lead to an increase in muscle mass and hand grip strength in Phase IIa cancer cachexia trial. 113 In patients with liver cirrhosis, higher serum myostatin levels were associated with muscle mass loss, hyperammonemia, and impaired protein synthesis, as well as impaired survival.…”