• Treatment with metformin increases muscle mass, decreases muscle fat storage, and enhances exercise capacity in both sarcopenic mice and sarcopenic obese mice. 
  • Metformin decreases muscle inflammation by activating an enzyme called AMPK – a longevity-linked molecule known to increase fat metabolism and reduce inflammation.  

As we age, the structural integrity of our muscles inevitably deteriorates, making us weaker and frailer. Studies show that muscle tissue can fall by 30% in individuals aged 50 and older, with many succumbing to sarcopenia, characterized by an extensive decline in muscle mass and strength. Sarcopenia is becoming increasingly prevalent in aged individuals with obesity, another age-related ailment that increases the risk for conditions like heart disease and type 2 diabetes. Furthermore, research is showing that sarcopenia can piggyback off of the harmful effects of obesity, further driving muscle decline and increased fat build-up. 

Now, researchers from Chongqing Medical University in China report in the journal BBA – Molecular Basis of Disease that metformin – an FDA-approved drug originally designed to treat diabetes – mitigates age-related sarcopenia in sarcopenic mice (SM) and sarcopenic obese mice (SOM). Lyu and colleagues show that treating SM and SOM with metformin for five months increases muscle mass, lowers muscle fat storage, and boosts physical performance. Additionally, the investigators show metformin attenuates muscle inflammation through AMPK activation. 

Metformin’s Effects on Muscle, Fat, and Fitness

Individuals suffering from obese sarcopenia are likely to experience greater muscle deterioration and fat build-up, both of which hinder physical fitness. Furthermore, these health deficits are driven by systemic inflammation. Given that metformin has well-established anti-inflammatory properties, Lyu and colleagues examined whether metformin could improve the health of mice modeling sarcopenia and obese sarcopenia. 

The results showed that mice modeling obese sarcopenia exhibited more muscle tissue, less fat tissue, and greater grip strength than untreated controls following treatment with metformin. Although mice modeling sarcopenia displayed insignificant gains in muscle tissue following treatment, fat tissue decreased significantly, and grip strength was superior to untreated controls. Taken together, the initial findings suggest that metformin can enhance the health and physical fitness of sarcopenic obese mice by restoring muscle tissue and limiting fat build-up in muscle tissue. 

(Lyu et al., 2022 | BBA – Molecular Basis of Disease) Metformin increases muscle mass, reduces fat, and enhances grip strength. Metformin-treated sarcopenic obese mice (OHM) have more muscle tissue (left), less fat tissue (middle), and greater strength (right) than untreated controls (OHV). Metformin-treated sarcopenic mice (OCM) have less fat tissue and greater grip strength than untreated controls (OCV).  

Metformin Alleviates Muscle Inflammation

To further investigate whether metformin triggers anti-inflammatory effects to attenuate obese sarcopenia, Lyu and colleagues analyzed the activity of inflammatory molecules known to hinder muscle regeneration and insulin resistance – a common side effect of obesity that increases blood sugar levels and risk of diabetes. The results showed that metformin effectively reduced the activity of multiple pro-inflammatory molecules (TNF-α, IL-1β, IL-6) in the muscle of sarcopenic mice and sarcopenic obese mice. 

The investigators proceeded to explore the underlying mechanisms behind metformin’s anti-inflammatory effects. Although the literature has yet to fully elucidate metformin’s cellular mechanisms, evidence suggests that metformin’s effects result from the activation of AMPK, an enzyme with potent anti-oxidative and anti-inflammatory properties. With this in mind, Lyu and colleagues looked at the activity of AMPK following treatment. 

The findings showed that the muscle tissue of treated-sarcopenic mice and sarcopenic obese mice exhibited much higher AMPK activity than untreated controls that displayed greater levels of inflammatory molecules. Overall, the findings indicate that metformin alleviates muscle inflammation through AMPK activation. 

(Lyu et al., 2022 | BBA – Molecular Basis of Disease) Metformin activates AMPK. Metformin-treated sarcopenic mice (OCM) and sarcopenic obese mice (OHM) have higher AMPK levels than untreated controls (OCV, OHV). 

Metformin’s Role In Aging 

Metformin has been in the spotlight as an anti-aging drug for quite some time, as it has strong ties to several longevity-linked pathways. Although it was originally formulated to treat diabetes, animal studies have shown that metformin can delay aging, reverse age-related eye degeneration, prevent cognitive impairment, limit organ deterioration, and prolong lifespan. However, there is still controversy surrounding metformin’s ability to exert these effects in humans. The findings of this study further support metformin’s role in mitigating primary features of aging. That being said, clinical trials are needed to confirm its anti-aging properties.