Pharmacological strategies in lung cancer-induced cachexia: effects on muscle proteolysis, autophagy, structure, and weakness

Muscle wasting and cachexia are important systemic manifestations of highly prevalent conditions including cancer. Inflammation, oxidative stress, autophagy, ubiquitin-proteasome system, nuclear factor (NF)-kB, and mitogen activated protein kinases (MAPK) are involved in the pathophysiology of cancer cachexia. Currently available treatment is limited and data demonstrating effectiveness in in vivo models are lacking. Our objectives were to explore in respiratory and limb muscles of lung cancer (LC) cachectic mice whether proteasome, NF-kB, and MAPK inhibitors improve muscle mass and function loss through several molecular mechanisms. Body and muscle weights, limb muscle force, protein degradation and the ubiquitin-proteasome system, signaling pathways, oxidative stress and inflammation, autophagy, contractile and functional proteins, myostatin and myogenin, and muscle structure were evaluated in the diaphragm and gastrocnemius of LC (LP07 adenocarcinoma) bearing cachectic mice (BALB/c), with and without concomitant treatment with NF-kB (sulfasalazine), MAPK (U0126), and proteasome (bortezomib) inhibitors. Compared to control animals, in both respiratory and limb muscles of LC cachectic mice: muscle proteolysis, ubiquitinated proteins, autophagy, myostatin, protein oxidation, FoxO-1, NF-kB and MAPK signaling pathways, and muscle abnormalities were increased, while myosin, creatine kinase, myogenin, and slow- and fast-twitch muscle fiber size were decreased. Pharmacological inhibition of NF-kB and MAPK, but not the proteasome system, induced in cancer-induced cachectic animals, a substantial restoration of muscle mass and force through a decrease in muscle protein oxidation and catabolism, myostatin, and autophagy, together with a greater content of myogenin, and contractile and functional proteins. These findings may offer new therapeutic strategies in cancer-induced cachexia.Fil: Chacon Cabrera, Alba. Universitat Pompeu Fabra; España. Universidad Carlos III de Madrid. Instituto de Salud; EspañaFil: Fermoselle, Clara. Universitat Pompeu Fabra; España. Universidad Carlos III de Madrid. Instituto de Salud; EspañaFil: Urtreger, Alejandro Jorge. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Mateu Jimenez, Mercè. Universidad Carlos III de Madrid. Instituto de Salud; España. Universitat Pompeu Fabra; EspañaFil: Diament, Miriam. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología; ArgentinaFil: Bal, Elisa Dora. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Sandri, Marco. Università di Padova; ItaliaFil: Barreiro, Eshter. Universitat Pompeu Fabra; España. Universidad Carlos III de Madrid. Instituto de Salud; Españ