Sirtuin 6 inhibition protects against glucocorticoid-induced skeletal muscle atrophy by regulating IGF/PI3K/AKT signaling

• Autores: Mishra, Sneha; Cosentino, Claudia; Tamta, Ankit Kumar; Khan, Danish; Srinivasan, Shalini; Ravi, Venkatraman; Abbotto, Elena; Arathi, Bangalore Prabhashankar; Kumar, Shweta; Jain, Aditi; Ramaian, Anand S.; Kizkekra, Shruti M.; Rajagopal, Raksha; Rao, Swathi; Krishna, Swati; Asirvatham Jeyaraj, Ninitha; Haggerty, Elizabeth R.; Silberman, Dafne Magalí; Kurland, Irwin J.; Veeranna, Ravindra P.; Jayavelu, Tamilselvan; Bruzzone, Santina; Mostoslavsky, Raul; Sundaresan, Nagalingam R.
• Año de publicación: 2022
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: SIRT6; MÚSCULO; VÍA IGF/PI3K/AKT
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

Chronic activation of stress hormones such as glucocorticoids leads to skeletal muscle wasting in mammals. However, the molecular events that mediate glucocorticoid-induced muscle wasting are not well understood. Here, we show that SIRT6, a chromatin-associated deacetylase indirectly regulates glucocorticoid-induced muscle wasting by modulating IGF/PI3K/AKT signaling. Our results show that SIRT6 levels are increased during glucocorticoid-induced reduction of myotube size and during skeletal muscle atrophy in mice. Notably, overexpression of SIRT6 spontaneously decreases the size of primary myotubes in a cell-autonomous manner. On the other hand, SIRT6 depletion increases the diameter of myotubes and protects them against glucocorticoid-induced reduction in myotube size, which is associated with enhanced protein synthesis and repression of atrogenes. In line with this, we find that muscle-specific SIRT6 deficient mice are resistant to glucocorticoid-induced muscle wasting. Mechanistically, we find that SIRT6 deficiency hyperactivates IGF/PI3K/AKT signaling through c-Jun transcription factor-mediated increase in IGF2 expression. The increased activation, in turn, leads to nuclear exclusion and transcriptional repression of the FoxO transcription factor, a key activator of muscle atrophy. Further, we find that pharmacological inhibition of SIRT6 protects against glucocorticoid-induced muscle wasting in mice by regulating IGF/PI3K/AKT signaling implicating the role of SIRT6 in glucocorticoid-induced muscle atrophy.
Fil: Mishra, Sneha. No especifíca;
Fil: Cosentino, Claudia. Harvard Medical School; Estados Unidos
Fil: Tamta, Ankit Kumar. No especifíca;
Fil: Khan, Danish. No especifíca;
Fil: Srinivasan, Shalini. No especifíca;
Fil: Ravi, Venkatraman. No especifíca;
Fil: Abbotto, Elena. Università degli Studi di Genova; Italia
Fil: Arathi, Bangalore Prabhashankar. No especifíca;
Fil: Kumar, Shweta. No especifíca;
Fil: Jain, Aditi. No especifíca;
Fil: Ramaian, Anand S.. No especifíca;
Fil: Kizkekra, Shruti M.. No especifíca;
Fil: Rajagopal, Raksha. No especifíca;
Fil: Rao, Swathi. No especifíca;
Fil: Krishna, Swati. No especifíca;
Fil: Asirvatham Jeyaraj, Ninitha. Indian Institute of Technology; India
Fil: Haggerty, Elizabeth R.. Harvard Medical School; Estados Unidos
Fil: Silberman, Dafne Magalí. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina
Fil: Kurland, Irwin J.. No especifíca;
Fil: Veeranna, Ravindra P.. No especifíca;
Fil: Jayavelu, Tamilselvan. No especifíca;
Fil: Bruzzone, Santina. Università degli Studi di Genova; Italia
Fil: Mostoslavsky, Raul. Harvard Medical School; Estados Unidos
Fil: Sundaresan, Nagalingam R.. No especifíca;