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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #331167
Title: The AMPK-related kinase SNARK regulates muscle mass and myocyte survival

Author
item LESSARD, SARAH - Joslin Diabetes Center
item RIVAS, DONATO - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item SO, KAWAI - Joslin Diabetes Center
item KOH, HO-JIN - Joslin Diabetes Center
item QUEIROZ, ANDRE LIMA - Joslin Diabetes Center
item HIRSHMAN, MICHAEL - Joslin Diabetes Center
item FIELDING, ROGER - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item GOODYEAR, LAURIE - Joslin Diabetes Center

Submitted to: Journal of Clinical Investigation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/12/2015
Publication Date: 12/21/2015
Citation: Lessard, S., Rivas, D.A., So, K., Koh, H., Queiroz, A., Hirshman, M.F., Fielding, R.A., Goodyear, L.J. 2015. The AMPK-related kinase SNARK regulates muscle mass and myocyte survival. Journal of Clinical Investigation. 126(2):560-570. doi:10.1172/jc179197.

Interpretive Summary: The maintenance of skeletal muscle mass is critical for sustaining health; however, the mechanisms responsible for muscle loss with aging and chronic diseases, such as diabetes and obesity, are poorly understood. We found that the amount of a member of the AMPK-related kinase family (an important regulator of energy use in the cell), the SNF1-AMPK-related kinase (SNARK, also known as NUAK2), increased in fully developed muscle cells. The amount of SNARK also increased in skeletal muscles from young mice exposed to energy stressors and in muscles from healthy older human subjects. The amount of SNARK in muscle with mature muscle cells and energy stressors suggests that SNARK may function in the maintenance of muscle mass.

Technical Abstract: The maintenance of skeletal muscle mass is critical for sustaining health; however, the mechanisms responsible for muscle loss with aging and chronic diseases, such as diabetes and obesity, are poorly understood. We found that expression of a member of the AMPK-related kinase family, the SNF1-AMPK-related kinase (SNARK, also known as NUAK2), increased with muscle cell differentiation. SNARK expression increased in skeletal muscles from young mice exposed to metabolic stress and in muscles from healthy older human subjects. The regulation of SNARK expression in muscle with differentiation and physiological stress suggests that SNARK may function in the maintenance of muscle mass. Consistent with this hypothesis, decreased endogenous SNARK expression (using siRNA) in cultured muscle cells resulted in increased apoptosis and decreased cell survival under conditions of metabolic stress. Likewise, muscle-specific transgenic animals expressing a SNARK dominant-negative inactive mutant (SDN) had increased myonuclear apoptosis and activation of apoptotic mediators in muscle. Moreover, animals expressing SDN had severe, age-accelerated muscle atrophy and increased adiposity, consistent with sarcopenic obesity. Reduced SNARK activity, in vivo and in vitro, caused downregulation of the Rho kinase signaling pathway, a key mediator of cell survival. These findings reveal a critical role for SNARK in myocyte survival and the maintenance of muscle mass with age.