Metformin is a commonly prescribed medication used to treat type 2 diabetes. It works by reducing glucose production in the liver and improving the body’s response to insulin. While the effects on blood sugar levels are well known, metformin also appears to have some direct and indirect effects on skeletal muscle.
How Does Metformin Work?
Metformin belongs to a class of medications called biguanides. It works in a few ways:
- Reduces the amount of glucose released by the liver
- Increases insulin sensitivity, allowing insulin to be more effective at bringing glucose into cells
- Reduces glucose absorption in the intestines
- Inhibits mitochondrial respiration, which reduces energy production and lowers blood sugar
By improving insulin sensitivity and decreasing liver glucose output, metformin enables the body to better utilize insulin and remove glucose from the bloodstream. This results in lower blood sugar levels.
Effects of Metformin on Muscles
Skeletal muscle is one of the major sites of glucose metabolism in the body. Given metformin’s mechanisms of action, it’s not surprising that it has some direct and indirect effects on muscle:
Increased Glucose Uptake
By increasing insulin sensitivity, metformin enables muscles to take up more glucose from the bloodstream. This can enhance glycogen storage and provide muscles with more fuel for energy production.
Altered Mitochondrial Function
Metformin inhibits complex I of the mitochondrial electron transport chain. This reduces mitochondrial oxygen consumption and ATP production. While the implications of this are still being studied, it may impact muscle energy metabolism.
AMPK Activation
Metformin activates AMP-activated protein kinase (AMPK), an enzyme involved in energy homeostasis. AMPK activation may stimulate glucose uptake, fat oxidation, and mitochondrial biogenesis in muscle cells.
Improved Insulin Signaling
By enhancing insulin sensitivity, metformin may amplify insulin signaling pathways involved in protein synthesis and inhibit protein breakdown in muscle.
Potential Increase in Muscle Mass
Some studies indicate metformin may increase muscle mass and strength, potentially by improving insulin-mediated anabolic signaling. However, findings have been mixed.
Metformin and Muscle Glycogen
Muscle glycogen is the storage form of glucose in skeletal muscle. It serves as an important energy source during exercise. Metformin’s effects on muscle glycogen levels have been examined in several studies:
- One study in men with type 2 diabetes found 6 months of metformin treatment increased insulin-stimulated muscle glycogen synthesis by over 50%.
- However, other trials found no significant difference in muscle glycogen levels between diabetics treated with metformin versus placebo.
- A few studies reported lower resting muscle glycogen content in those taking metformin versus controls.
- Metformin does not appear to significantly alter glycogen utilization during moderate or high-intensity exercise.
Overall, metformin may increase glycogen synthesis rates, but effects on absolute glycogen levels are less clear. More research is needed on how metformin influences muscle glycogen content and utilization.
Metformin and Muscle Mitochondria
Mitochondria are often called the “powerhouses” of the cell due to their role in energy production. Metformin seems to have mixed effects on muscle mitochondria:
- Metformin reduces mitochondrial oxygen consumption in isolated muscle cells by inhibiting complex I of the electron transport chain.
- Some studies show metformin increases mitochondrial biogenesis and expression of genes involved in oxidative metabolism.
- Other research found no significant differences in mitochondrial content or enzyme activities in the muscles of metformin-treated diabetic patients.
- Overall, metformin may impair mitochondrial respiration but also trigger adaptations that enhance mitochondrial function long-term.
Metformin and Exercise Performance
Some research has examined how metformin affects exercise capacity and performance:
- In one study, metformin improved cardiorespiratory fitness in individuals with prediabetes doing aerobic interval training.
- However, other trials found metformin did not improve VO2 max or cycling time trial performance versus placebo.
- A few studies report enhanced strength gains and muscle mass from resistance training when combined with metformin.
- But other research shows no added benefit on muscle mass or strength with metformin plus strength training.
Current evidence does not conclusively show metformin enhances fitness or performance with exercise training. More studies are warranted.
Metformin and Muscle Breakdown
Muscle breakdown occurs when the rate of muscle protein degradation exceeds protein synthesis. Metformin may help prevent excessive muscle catabolism by:
- Boosting insulin-mediated inhibition of muscle protein breakdown
- Suppressing proteolytic pathways induced by insulin deficiency
- Activating AMPK, which stimulates protein synthesis and mitigates catabolism
Research on metformin’s anti-catabolic effects in muscle is limited. But by improving insulin signaling and action, metformin may help conserve muscle mass during periods of metabolic stress.
Metformin and Sarcopenia
Sarcopenia refers to the age-related loss of muscle mass and strength. A few mechanisms by which metformin could potentially combat sarcopenia include:
- Increasing insulin sensitivity and muscle protein synthesis
- Reducing insulin resistance-associated inflammation
- Activating pathways involved in muscle growth like AMPK and mTOR
- Enhancing mitochondrial function and oxidative capacity
Initial research shows some promise for metformin to treat sarcopenia. One study found older adults with diabetes had less lean mass loss over 3 years when taking metformin. More studies are needed to explore this potential application.
Metformin Side Effects in Muscle
While relatively safe, metformin can cause some side effects involving skeletal muscle:
- Myalgia: Up to 10% of metformin users report muscle aches and pains.
- Cramps: Leg cramps are a reported side effect, likely from metformin’s impacts on electrolytes.
- Weakness: Feeling weak is an uncommon side effect, possibly due to mitochondrial effects.
- Lactic acidosis: This serious condition causes lactate buildup in muscles. It is very rare with metformin use.
These side effects tend to be mild but can negatively impact muscle functioning. Alert your doctor if muscle symptoms do not resolve.
Conclusion
Metformin has several effects on skeletal muscle metabolism and physiology:
- It increases glucose uptake into muscle by improving insulin sensitivity.
- It may alter mitochondrial function, both impairing and boosting it.
- It activates AMPK, influencing muscle protein balance.
- It could potentially increase muscle mass but effects are inconclusive.
- It may raise muscle glycogen synthesis but often does not alter glycogen content.
- It does not clearly improve exercise performance.
- It may have anti-catabolic effects by improving insulin action.
- It could potentially help counteract sarcopenia.
While promising in theory, more research is still needed to clarify metformin’s impacts on muscle mass and function across different populations. But by improving insulin sensitivity and mitochondrial function, metformin likely exerts both direct and indirect effects on skeletal muscle metabolism and physiology.