The AMPK-related kinase SNARK regulates muscle mass and myocyte survival
Sarah J. Lessard, … , Roger A. Fielding, Laurie J. Goodyear
Sarah J. Lessard, … , Roger A. Fielding, Laurie J. Goodyear
Published December 21, 2015
Citation Information: J Clin Invest. 2016;126(2):560-570. https://doi.org/10.1172/JCI79197.
View: Text | PDF
Research Article Muscle biology

The AMPK-related kinase SNARK regulates muscle mass and myocyte survival

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.

Authors

Sarah J. Lessard, Donato A. Rivas, Kawai So, Ho-Jin Koh, André Lima Queiroz, Michael F. Hirshman, Roger A. Fielding, Laurie J. Goodyear

×

Figure 5

Muscle morphology in SNARK transgenic mice.

Options: View larger image (or click on image) Download as PowerPoint
Muscle morphology in SNARK transgenic mice. (A) Images of gastrocnemius ...
(A) Images of gastrocnemius and TA muscles taken from 58-week-old SDN mice, SWT mice, and wild-type littermates. (B) Cross sections (6 μm) were taken from TA muscles, muscle sections were stained with anti-laminin (white), and nuclei were visualized with DAPI (blue). Glycolytic fibers were stained with anti–myosin heavy chain IIB (green). Compared with those of wild-type and SWT mice, SDN muscles displayed small, atrophic fibers (yellow, asterisks) and large fibers with centralized nuclei (yellow, arrows) indicating muscle regeneration. Original magnification, ×200; scale bar: 50 μm. (C) The number of glycolytic (type IIB) and oxidative (unstained) fibers were counted for each section, and (D) the CSA of each fiber was measured. (E) Mean CSA was calculated for oxidative and glycolytic fibers from each genotype, and (F) the size distribution of glycolytic fibers was plotted. *P < 0.05 vs. control determined by 1-way ANOVA and Bonferroni post-hoc testing. Data for all panels were quantified from sections taken from n = 5 animals per group. Error bars indicate mean ± SEM.