VK2 regulates slow-twitch muscle fibers expression and mitochondrial function via SIRT1/SIRT3 signaling

Abstract

Objectives: Skeletal muscle accounts for 80% of whole body insulin-stimulated glucose uptake, and it plays a key role in preventing and curing obesity and insulin resistance (IR). Vitamin K2 (VK2) plays a beneficial role in improving mitochondrial function through SIRT1 signaling in high-fat diet (HFD)-induced mice and palmitate acid (PA)-treated C₂C₁₂ cells. A previous study also found VK2 increases oxidative muscle fibers and decreases glycolytic muscle fibers in obesity-induced mice, however, the underlying molecular mechanism of effect of VK2 on increasing oxidative fibers have not been well established.

Methods: C57BL/6 male mice were induced IR using HFD fed. Animals received HFD for eight weeks, and different doses of VK2 were supplemented by oral gavage for the last eight weeks were randomly and equally divided into seven groups. C₂C₁₂ cells were exposed to different doses of PA for 16 h to mimic insulin resistance in vivo. Skeletal muscle types and mitochondrial function evaluated. C₂C₁₂ cells were transfected with SIRT1 siRNA.

Results: The present study first revealed that VK2 intervention also alleviated plasma non-esterified fatty acid levels that contribute to obesity-induced IR, VK2 administration also could effectively increase the proportion of slow-twitch fibers by improving mitochondrial function via SIRT1 signaling pathway in both HFD-fed mice and PA-exposed cells. However, the benefits of VK2 were abrogated in C₂C₁₂ transfected with SIRT1 siRNA in PA-treated C₂C₁₂ cells. Thus, SIRT1 is partially required for VK2 improvement the proportion of slow-twitch fiber in PA-treated C₂C₁₂ cells.

Conclusion: Naturally occurring VK2 increases slow-twitch fibers by improving mitochondrial function and decreasing non-esterified fatty acid levels via partially SIRT1/SIRT3 signaling pathway. These data have potential importance for the therapy for a number of muscular and neuromuscular diseases in humans.

Keywords: Mitochondrial function; Muscle fibers; SIRT1 signaling; Vitamin K(2).