Vitamin K2 Alleviates Insulin Resistance Associated Skeletal Muscle Atrophy via the AKT/mTOR Signalling Pathway

Skeletal muscle atrophy and insulin resistance (IR) aggravate each other. Vitamin K2 (VK2) exhibits beneficial effects on IR, but whether it improves IR associated skeletal muscle atrophy remains insufficiently understood. This study aims to investigate the effects of VK2 on IR associated skeletal muscle atrophy in high-fat diet (HFD) mice and type 2 diabetes mellitus (T2DM) patients and explore the potential mechanisms.

VK2 was administered to HFD-fed C57BL/6 mice for 16 weeks. Grip strength, exercise capacity, oral glucose tolerance test (OGTT) and body fat rate were measured. Animals were sacrificed, and skeletal muscle and serum samples were collected to analyse muscle atrophy, glucose and lipid levels. The gene expression profile of skeletal muscle was determined by RNA sequencing. C2C12 cells were cultured for gene knockdown and overexpression experiments. For the randomized controlled trial (RCT), a total of 102 T2DM patients aged 50-80 years were recruited and randomly assigned to receive yogurt (one cup per day) with or without VK2 fortification (90 μg/day) for 6 months. Grip strength, skeletal muscle mass (SM), skeletal muscle mass index (SMI), 6-m gait speed (6-m GS), glycated haemoglobin (HbA1c), fasting blood glucose (FBG), fasting insulin (FINS) and homeostasis model assessment of insulin resistance (HOMA-IR) were measured at 0, 3 and 6 months, respectively.

VK2 significantly improved grip strength (p < 0.01) and exercise capacity (all p < 0.05) in HFD-fed mice. At the tissue level, VK2 increased skeletal muscle mass (p < 0.05) and cross-sectional area of muscle fibres (p < 0.05), while reducing the proportion of fast-twitch fibres (p < 0.01). VK2 treatment decreased body fat rate (p < 0.01) accompanied by enhanced whole-body energy metabolism. VK2 also diminished the glucolipid metabolism parameters, including glucose (p < 0.01), HOMA-IR (p < 0.01) and serum lipid levels. Regarding the mechanism, VK2 promoted the phosphorylation of proteins in the FAK-AKT-mTOR-P70S6K pathway by targeting Ccn2, thereby enhancing protein synthesis of C2C12 myotubes. In the RCT study, VK2 supplementation significantly increased grip strength (p_{treatment × time} = 0.017), SM (p_{treatment × time} = 0.001), SMI (p_{treatment × time} < 0.001) and decreased HbA1c (p_{treatment × time} < 0.001), FBG (p_{treatment × time} = 0.056), FINS (p_{treatment × time} < 0.001), and HOMA-IR (p_{treatment × time} < 0.001) in T2DM subjects.

Our findings demonstrated the beneficial effects of VK2 on insulin resistance related skeletal muscle atrophy by promoting protein synthesis via the AKT/mTOR pathway.