T.P.36 Hepatocyte growth factor reverses atrophy by inducing protein synthesis in mice

Abstract

Abstract We investigated if hepatocyte growth factor (HGF) and leukemia inhibitory factor (LIF) can enhance muscle regeneration and thus increase muscle mass in a hypoxia-induced atrophy mouse model. B10 mice were exposed to 2 weeks of hypoxia to induce muscle atrophy before starting treatment. Hypoxia was continued during treatment with HGF/LIF ( N = 13) or placebo ( N = 14). Treatment was given as intraperitoneal injections every second day alternating between HGF and LIF for 2 weeks. Hypoxic exposure resulted in an average drop of 30% in bodyweight and 20% in muscle weight. Dividing satellite cells were twofold increased in the treatment group compared to control and the PI3K/Akt pathway significantly induced to a 100-fold activation of p70S6K, known for its implication in protein synthesis. We found that HGF treatment lead to activation of the Akt/mTOR/p70S6K protein synthesis pathway, up-regulation of the myogenic transcription factors MyoD and myogenin and subsequently the negative growth control factor, myostatin and atrophy markers MAFbx and MuRF1. Furthermore, we found that HGF/LIF treatment of muscle atrophy models lead to an increase in lean muscle mass: Tibialis anterior weight increased by 9% and extensor digitorium longus by 18%. Finally we demonstrate that myostatin regulates satellite cell activation and myogenesis in vivo following HGF/LIF treatment, consistent with previous findings in vitro. Our results suggest a novel in vivo pharmacological treatment with HGF, directed specifically at activating the satellite cells. This treatment could potentially be applied to many conditions that feature muscle wasting to increase muscle bulk and strength.