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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.

SUBMITTER: Lessard SJ

PROVIDER: S-EPMC4731174 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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

Lessard Sarah J SJ Rivas Donato A DA So Kawai K Koh Ho-Jin HJ Queiroz André Lima AL Hirshman Michael F MF Fielding Roger A RA Goodyear Laurie J LJ

The Journal of clinical investigation 20160201 2

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 h ...[more]

PMID: 26690705

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Project description:Myocyte differentiation involves complex interactions between signal transduction pathways and transcription factors. The estrogen-related receptors (ERRs) regulate energy substrate uptake, mitochondrial respiration, and biogenesis and may target structural gene programs in striated muscle. However, ERRα's role in regulating myocyte differentiation is not known. ERRα and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) are coordinately upregulated with metabolic and skeletal muscle-specific genes early in myogenesis. We analyzed effects of ERRα overexpression and loss of function in myogenic models. In C2C12 myocytes ERRα overexpression accelerated differentiation, whereas XCT790 treatment delayed myogenesis and resulted in myotubes with fewer mitochondria and disorganized sarcomeres. ERRα-/- primary myocytes showed delayed myogenesis, resulting in structurally immature myotubes with reduced sarcomeric assembly and mitochondrial function. However, sarcomeric and metabolic gene expression was unaffected or upregulated in ERRα-/- cells. Instead, ERRα-/- myocytes exhibited aberrant ERK activation early in myogenesis, consistent with delayed myotube formation. XCT790 treatment also increased ERK phosphorylation in C2C12, whereas ERRα overexpression decreased early ERK activation, consistent with the opposing effects of these treatments on differentiation. The transient induction of MAP kinase phosphatase-1 (MKP-1), which mediates ERK dephosphorylation at the onset of myogenesis, was lost in ERRα-/- myocytes and in XCT790-treated C2C12. The ERRα-PGC-1α complex activates the Dusp1 gene, which encodes MKP-1, and ERRα occupies the proximal 5' regulatory region during early differentiation in C2C12 myocytes. Finally, treatment of ERRα-/- myocytes with MEK inhibitors rescued normal ERK signaling and myogenesis. Collectively, these data demonstrate that ERRα is required for normal skeletal myocyte differentiation via modulation of MAP kinase signaling.

Dataset Information

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

Publications

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

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