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

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 gluco...

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Detalles Bibliográficos
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.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:Argentina
Institución:Consejo Nacional de Investigaciones Científicas y Técnicas
Repositorio:CONICET Digital (CONICET)
Idioma:inglés
OAI Identifier:oai:ri.conicet.gov.ar:11336/211228
Acceso en línea:http://hdl.handle.net/11336/211228
Access Level:acceso abierto
Palabra clave:SIRT6
MÚSCULO
VÍA IGF/PI3K/AKT
https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
Descripción
Sumario: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.

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