Skeletal muscle is the body’s main consumer of glucose derived from food.
Muscle Fiber Types
Skeletal muscle is composed of two types of muscle fiber: Type I (slow-twitch) and Type II (fast-twitch).
Type I fibers contract slowly and can maintain contraction over long periods of time. They are rich in mitochondria and myoglobin and are well vascularized. These fibers rely mostly on aerobic metabolism to make the ATP that fuels cells. Type I muscle fibers are fatigue-resistant and efficient—great for supporting posture, distance running, cycling and any activity that needs steady output.
Type II fibers contract quickly, produce more force and power, but also fatigue more quickly. They have fewer mitochondria and less vasculature and rely more on anaerobic pathways like glycolysis (using glucose without oxygen).
Type I muscle fibers are smaller in diameter and generate less peak force but excel at endurance and heat management. Type II fibers are typically larger, produce more force and speed and handle explosive tasks like sprinting, jumping or heavy lifting.
Most muscles are a mix of fiber types, and genetics sets the starting ratio of Type l to Type ll, but fibers are adaptable. With aging and disuse, Type II fibers tend to atrophy more, which is one reason that power declines faster than endurance.
Another distinction important for this story: Type I fibers are more insulin-sensitive than Type II fibers. Additionally, these fiber types differ in different body types.
The Hypothesis
A study by Shi et al., “VEGF-B-mediated myofiber types involved in high-fat diet-induced hyperglycemia through PKA-NFATs signaling pathway” addressed whether vascular endothelial growth factor-B (VEGF-B)—particularly the VEGF-B186 isoform—helps drive the fiber-type shifts and metabolic defects seen in obesity and type 2 diabetes (T2D).
In obesity and type 2 diabetes (T2D), many studies report a shift away from oxidative, insulin-sensitive fibers (Types I and IIa) toward more glycolytic fibers (notably IIx in humans). That shift comes with lower capillary density and fewer mitochondria per fiber, which together mean less delivery of insulin/glucose and less capacity to burn fuels. It’s not universal across every muscle or cohort, but the trend helps explain why whole-body glucose disposal falls even when muscle mass looks unchanged.
At the cellular level, insulin signaling and substrate handling are altered. Oxidative fibers typically carry more GLUT4, richer capillary supply, and higher mitochondrial enzyme activity. In obesity/T2D, mitochondrial content and oxidative phosphorylation decline, fatty-acid oxidation lags and lipid by-products (e.g., diacylglycerols, ceramides) accumulate. Those lipids activate kinases that phosphorylate proteins at inhibitory sites, blunting the PI3K→Akt pathway that normally moves GLUT4 to the membrane. Net effect: less insulin-stimulated glucose uptake, lower glycogen synthase activity, and a tilt toward glycolysis that still fails to compensate under physiologic loads.
Vascular control is another choke point. People with insulin resistance often show impaired nitric-oxide–mediated vasodilation, microvascular rarefaction, and diminished “microvascular recruitment” after a meal or insulin infusion. Fewer perfused capillaries means slower delivery of insulin and glucose to the interstitium and fewer exchange surfaces right next to the fibers—particularly harmful for Type I/IIa fibers that are built to use that supply. Add low-grade inflammation and ER/oxidative stress, and you get a milieu that maintains the fast/glycolytic phenotype and keeps GLUT4 trafficking subdued.
The authors proposed that elevated VEGF-B, especially VEGF-B186, suppresses Type I fiber formation and thus impairs glucose handling through a defined signaling axis.
Testing the Hypothesis
In vivo, the researchers compared Vegfb knockout mice to wild-type animals by feeding either normal or high-fat diets, then profiled muscles by RNA-seq and double immunofluorescence to quantify Type I vs. Type II fibers.
In vitro, they built a “continuous single-dose” model in differentiating C2C12 myoblasts: each day at media change, they added VEGF-B167 or VEGF-B186 to better mimic physiological persistence and the higher circulating levels reported in T2DM.
They then probed mechanism with PKA activators and NFATc1/c2 overexpression and assessed mitochondrial and glycolytic function plus glucose transporter expression. Notably, this daily, steady-level dosing regime is a unique twist that aligns the cell model with the in-vivo temporal exposure the authors were trying to mirror.
Results
The researchers found that knocking out Vegfb protected muscle fiber composition and metabolism under dietary stress. Compared with high-fat–fed wild-type mice, Vegfb-/- animals retained more Type I fibers and showed lower fasting glucose and improved lipid profiles.
In cells, VEGF-B effects were dose- and isoform-dependent. Low doses of either isoform promoted myoblast differentiation and fusion, but high doses—especially of VEGF-B186—suppressed myoblast expression, myotube formation, and most prominently, Type I fiber markers compared with Type II fiber markers.
Pharmacologic PKA activation or NFATc1/c2 overexpression reversed these effects; NFATc1 gave the strongest rescue. VEGF-B186 also downregulated GLUT4 and reduced insulin-stimulated glucose uptake, while sparing glycolysis and only denting mitochondrial spare respiratory capacity—again rescued by PKA/NFAT interventions.
To quantify basal and insulin-stimulated glucose uptake in differentiated C2C12 cell myotubes, the researchers used the Glucose Uptake-Glo™ Assay (Cat.# J1341). Using this assay, chronic high-dose VEGF-B186 depressed insulin-stimulated uptake, and both PKA activators and NFATc1/c2 overexpression restored it.
Conclusion
The data show VEGF-B—particularly VEGF-B186—as a regulator that tilts muscle away from the Type I, insulin-sensitive phenotype and blunts glucose handling. That makes VEGF-B186 inhibition (antibodies or other blockers) an intriguing therapeutic angle for obesity/T2DM, where slow-twitch Type I fiber content is typically depleted.
As the authors note, these are mouse and C2C12 cell results; confirmation in primary human myoblasts and in clinical contexts will be important next steps. Still, the fiber-type maps and the integrative pathway diagram shown in this paper tell the same story: less nuclear NFAT, fewer Type I fibers, lower GLUT4, poorer glucose uptake—unless you restore PKA–NFAT signaling.
Reference
Shi, et al. (2025) VEGF-B-mediated myofiber types involved in high-fat diet-induced hyperglycemia through PKA-NFATs signaling pathway. Stem Cell Res. Ther. 16(1) 336.
doi: 10.1186/s13287-025-04455-7
Kari Kenefick
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