期刊
DIABETOLOGIA
卷 61, 期 2, 页码 424-432出版社
SPRINGER
DOI: 10.1007/s00125-017-4451-8
关键词
AICAR; AMPK; Focal adhesion kinase; Gene silencing; Glycogen synthesis; Insulin; Lipid oxidation; Metabolic flexibility; Open-muscle biopsy; Skeletal muscle
资金
- Strategic Research Programme in Diabetes at Karolinska Institutet
- European Research Council (ICEBERG) [ERC-2009-AdG233285]
- Swedish Research Council [2011-3550]
- Swedish Diabetes Foundation [DIA2012-082, DIA2012-047]
- Swedish Foundation for Strategic Research [SRL10-0027]
- Diabetes Wellness Sweden
- Novo Nordisk Foundation
- Stockholm County Council
- Novo Nordisk Fonden [NNF14OC0009941, NNF15OC0016536, NNF14OC0010883, NNF13OC0005961, NNF15SA0018346, NNF14OC0011493] Funding Source: researchfish
Aims/hypothesis Insulin-mediated signals and AMP-activated protein kinase (AMPK)-mediated signals are activated in response to physiological conditions that represent energy abundance and shortage, respectively. Focal adhesion kinase (FAK) is implicated in insulin signalling and cancer progression in various non-muscle cell types and plays a regulatory role during skeletal muscle differentiation. The role of FAK in skeletal muscle in relation to insulin stimulation or AMPK activation is unknown. We examined the effects of insulin or AMPK activation on FAK phosphorylation in human skeletal muscle and the direct role of FAK on glucose and lipid metabolism. We hypothesised that insulin treatment and AMPK activation would have opposing effects on FAK phosphorylation and that gene silencing of FAK would alter metabolism. Methods Human muscle was treated with insulin or the AMPK-activating compound 5-aminoimadazole-4-carboxamide ribonucleotide (AICAR) to determine FAK phosphorylation and glucose transport. Primary human skeletal muscle cells were used to study the effects of insulin or AICAR treatment on FAK signalling during serum starvation, as well as to determine the metabolic consequences of silencing the FAK gene, PTK2. Results AMPK activation reduced tyrosine phosphorylation of FAK in skeletal muscle. AICAR reduced p-FAK(Y397) in isolated human skeletal muscle and cultured myotubes. Insulin stimulation did not alter FAK phosphorylation. Serum starvation increased AMPK activation, as demonstrated by increased p-ACC(S222), concomitant with reduced p-FAK(Y397). FAK signalling was reduced owing to serum starvation and AICAR treatment as demonstrated by reduced p-paxillin(Y118). Silencing PTK2 in primary human skeletal muscle cells increased palmitate oxidation and reduced glycogen synthesis. Conclusions/interpretation AMPK regulates FAK signalling in skeletal muscle. Moreover, siRNA-mediated FAK knockdown enhances lipid oxidation while impairing glycogen synthesis in skeletal muscle. Further exploration of the interaction between AMPK and FAK may lead to novel therapeutic strategies for diabetes and other chronic conditions associated with an altered metabolic homeostasis.
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