Executive Summary
The Metformin to Augment Strength Training Effective Response in Seniors (MASTERS) trial was a randomized, double-blind, placebo-controlled multicenter study designed to determine if metformin could enhance the muscle-building effects of progressive resistance exercise training (PRT) in healthy individuals aged 65 and older. Contrary to the initial hypothesis that metformin's anti-inflammatory properties would augment muscle growth, the study found that metformin significantly blunts the hypertrophic response to resistance training.
Key findings include:
• Reduced Lean Mass Gains: Participants in the placebo group gained significantly more lean body mass (+1.95%) compared to those taking metformin (+0.41%).
• Inhibition of Muscle Growth: Placebo subjects experienced a 3.90% increase in thigh muscle mass, while the metformin group showed no significant gain (0.45%).
• Molecular Interference: Metformin increased AMPK signaling and blunted the activation of the mTORC1 pathway, a critical regulator of muscle protein synthesis.
• Strength Trends: While both groups gained strength, there was a consistent trend toward blunted gains in knee extension strength and power in the metformin group.
These results suggest that while metformin is a primary treatment for diabetes, it negatively impacts skeletal muscle adaptations to exercise in healthy older adults, likely by interfering with mitochondrial function and anabolic signaling pathways.
Study Overview and Methodology
Rationale and Hypothesis
Sarcopenia, the age-related loss of muscle mass, is highly correlated with disability and mortality. While PRT is the most effective therapy for sarcopenia, responses vary among individuals. Researchers hypothesized that metformin might improve this response by reducing chronic low-grade muscle inflammation and promoting anti-inflammatory M2 macrophage polarization.
Trial Design
The MASTERS trial was conducted at the University of Kentucky and the University of Alabama at Birmingham.
• Participants: 109 subjects randomized; 94 completed the study (46 Metformin; 48 Placebo).
• Demographics: Median age ~69.4 years; mean BMI 26.3; 56% female; predominantly high-functioning community-dwelling seniors.
• Dose: 1,700 mg/day of metformin or an identical placebo.
• Duration: 14 weeks of supervised PRT, including a 2-week drug wash-in and exercise ramp-up phase.
• Exercise Protocol: Supervised, variable-intensity, bilateral upper and lower body PRT performed three days per week.
Key Findings: Physiological and Functional Impact
Body Composition and Muscle Hypertrophy
The most significant impact of metformin was the suppression of muscle growth. While both groups saw a reduction in body fat percentage, the gains in lean mass were markedly different.
Strength and Power
Metformin treatment tended to inhibit functional improvements, though these results did not always reach the threshold for statistical significance (p < .05).
• Knee Extension (1RM): Placebo increased by 23.1%; Metformin increased by 15.3% (p = .055).
• Isometric Strength: Placebo increased by 11.8%; Metformin increased by 6.7% (p = .082).
• Peak Power: Placebo increased by 29.4%; Metformin increased by 14.3% (p = .064).
• Relative Strength: Gains (normalized to thigh mass) were similar between groups (Placebo 19.7% vs. Metformin 14.5%, p = .188).
Cellular and Molecular Analysis
Fiber-Specific Adaptations
• Fiber Hypertrophy: Interestingly, metformin did not significantly affect the cross-sectional area (CSA) of individual type I or type II muscle fibers. Researchers suggest that whole-muscle measures (CT/DXA) may be more reliable indicators of hypertrophy than fiber CSA due to lower sampling variance.
• Fiber Type Frequency: PRT typically causes a shift away from type I fibers. Metformin inhibited this shift; the placebo group saw a 6.06% decrease in type I fiber frequency, while the metformin group saw a non-significant increase of 2.50% (p = .007).
• Satellite Cells and Macrophages: Metformin had no significant effect on the accretion of satellite cells (muscle stem cells) or the abundance of M2 macrophages, indicating the drug's inhibitory effects occur through other mechanisms.
Signaling Pathways (AMPK vs. mTORC1)
The study identified a clear interaction between metformin and the molecular pathways governing muscle growth:
• AMPK Activation: Metformin increased basal AMPK signaling. Metformin-treated subjects showed a significantly larger increase in ACC phosphorylation (+42.2% vs. +6.2% in placebo, p = .035).
• mTORC1 Inhibition: Metformin appeared to blunt the anabolic mTORC1 pathway. Following PRT, RPS6 phosphorylation (a downstream target of mTORC1) increased by 73.1% in the placebo group but only 29.9% in the metformin group (p = .090).
• In Vitro Validation: In cultured human myotubes, metformin treatment blunted the phosphorylation of p70S6K1 (an immediate mTOR target) following electrical stimulation.
Clinical Implications and Conclusions
Interaction with Mitochondrial Function
Metformin is known to inhibit mitochondrial complex I. Researchers suggest that during the high metabolic demands of PRT, this inhibition may counteract the potential benefits of AMPK activation. This theory is supported by the finding that metformin blunted improvements in muscle density, suggesting it may interfere with the reduction of intramyocellular lipids (fat within the muscle).
General Health Outcomes
• Glucose Metabolism: Both groups improved insulin sensitivity and glucose tolerance through PRT; metformin did not provide additional benefits to these measures in this non-diabetic cohort.
• Adverse Events: Metformin was associated with a higher rate of gastrointestinal side effects (p = .002), though these did not lead to higher dropout rates or lower exercise compliance.
Final Conclusion
The MASTERS trial demonstrates that metformin negatively impacts the hypertrophic response to resistance training in healthy older individuals. While the drug remains a cornerstone for diabetes management, these results do not support the use of metformin to enhance the benefits of physical activity in healthy seniors. The findings suggest that metformin may "tame" the expectations of the drug as a treatment to extend healthspan when combined with exercise.
Source: Metformin Voids Benefits of Resistance Training
The Metformin to Augment Strength Training Effective Response in Seniors (MASTERS) trial was a randomized, double-blind, placebo-controlled multicenter study designed to determine if metformin could enhance the muscle-building effects of progressive resistance exercise training (PRT) in healthy individuals aged 65 and older. Contrary to the initial hypothesis that metformin's anti-inflammatory properties would augment muscle growth, the study found that metformin significantly blunts the hypertrophic response to resistance training.
Key findings include:
• Reduced Lean Mass Gains: Participants in the placebo group gained significantly more lean body mass (+1.95%) compared to those taking metformin (+0.41%).
• Inhibition of Muscle Growth: Placebo subjects experienced a 3.90% increase in thigh muscle mass, while the metformin group showed no significant gain (0.45%).
• Molecular Interference: Metformin increased AMPK signaling and blunted the activation of the mTORC1 pathway, a critical regulator of muscle protein synthesis.
• Strength Trends: While both groups gained strength, there was a consistent trend toward blunted gains in knee extension strength and power in the metformin group.
These results suggest that while metformin is a primary treatment for diabetes, it negatively impacts skeletal muscle adaptations to exercise in healthy older adults, likely by interfering with mitochondrial function and anabolic signaling pathways.
Study Overview and Methodology
Rationale and Hypothesis
Sarcopenia, the age-related loss of muscle mass, is highly correlated with disability and mortality. While PRT is the most effective therapy for sarcopenia, responses vary among individuals. Researchers hypothesized that metformin might improve this response by reducing chronic low-grade muscle inflammation and promoting anti-inflammatory M2 macrophage polarization.
Trial Design
The MASTERS trial was conducted at the University of Kentucky and the University of Alabama at Birmingham.
• Participants: 109 subjects randomized; 94 completed the study (46 Metformin; 48 Placebo).
• Demographics: Median age ~69.4 years; mean BMI 26.3; 56% female; predominantly high-functioning community-dwelling seniors.
• Dose: 1,700 mg/day of metformin or an identical placebo.
• Duration: 14 weeks of supervised PRT, including a 2-week drug wash-in and exercise ramp-up phase.
• Exercise Protocol: Supervised, variable-intensity, bilateral upper and lower body PRT performed three days per week.
Key Findings: Physiological and Functional Impact
Body Composition and Muscle Hypertrophy
The most significant impact of metformin was the suppression of muscle growth. While both groups saw a reduction in body fat percentage, the gains in lean mass were markedly different.
| Measure | Placebo Change | Metformin Change | Significance (Between Groups) |
|---|---|---|---|
| Total Lean Mass (DXA) | +1.95% | +0.41% | p = .003 |
| Thigh Muscle Mass (DXA) | +3.90% | +0.45% | p < .001 |
| Total Thigh Muscle Area (CT) | +6.43% | +2.27% | p = .005 |
| Normal Density Muscle Area (CT) | +10.5% | +4.16% | p = .001 |
| Muscle Density (HU) | +4.13% | +2.49% | p = .020 |
Strength and Power
Metformin treatment tended to inhibit functional improvements, though these results did not always reach the threshold for statistical significance (p < .05).
• Knee Extension (1RM): Placebo increased by 23.1%; Metformin increased by 15.3% (p = .055).
• Isometric Strength: Placebo increased by 11.8%; Metformin increased by 6.7% (p = .082).
• Peak Power: Placebo increased by 29.4%; Metformin increased by 14.3% (p = .064).
• Relative Strength: Gains (normalized to thigh mass) were similar between groups (Placebo 19.7% vs. Metformin 14.5%, p = .188).
Cellular and Molecular Analysis
Fiber-Specific Adaptations
• Fiber Hypertrophy: Interestingly, metformin did not significantly affect the cross-sectional area (CSA) of individual type I or type II muscle fibers. Researchers suggest that whole-muscle measures (CT/DXA) may be more reliable indicators of hypertrophy than fiber CSA due to lower sampling variance.
• Fiber Type Frequency: PRT typically causes a shift away from type I fibers. Metformin inhibited this shift; the placebo group saw a 6.06% decrease in type I fiber frequency, while the metformin group saw a non-significant increase of 2.50% (p = .007).
• Satellite Cells and Macrophages: Metformin had no significant effect on the accretion of satellite cells (muscle stem cells) or the abundance of M2 macrophages, indicating the drug's inhibitory effects occur through other mechanisms.
Signaling Pathways (AMPK vs. mTORC1)
The study identified a clear interaction between metformin and the molecular pathways governing muscle growth:
• AMPK Activation: Metformin increased basal AMPK signaling. Metformin-treated subjects showed a significantly larger increase in ACC phosphorylation (+42.2% vs. +6.2% in placebo, p = .035).
• mTORC1 Inhibition: Metformin appeared to blunt the anabolic mTORC1 pathway. Following PRT, RPS6 phosphorylation (a downstream target of mTORC1) increased by 73.1% in the placebo group but only 29.9% in the metformin group (p = .090).
• In Vitro Validation: In cultured human myotubes, metformin treatment blunted the phosphorylation of p70S6K1 (an immediate mTOR target) following electrical stimulation.
Clinical Implications and Conclusions
Interaction with Mitochondrial Function
Metformin is known to inhibit mitochondrial complex I. Researchers suggest that during the high metabolic demands of PRT, this inhibition may counteract the potential benefits of AMPK activation. This theory is supported by the finding that metformin blunted improvements in muscle density, suggesting it may interfere with the reduction of intramyocellular lipids (fat within the muscle).
General Health Outcomes
• Glucose Metabolism: Both groups improved insulin sensitivity and glucose tolerance through PRT; metformin did not provide additional benefits to these measures in this non-diabetic cohort.
• Adverse Events: Metformin was associated with a higher rate of gastrointestinal side effects (p = .002), though these did not lead to higher dropout rates or lower exercise compliance.
Final Conclusion
The MASTERS trial demonstrates that metformin negatively impacts the hypertrophic response to resistance training in healthy older individuals. While the drug remains a cornerstone for diabetes management, these results do not support the use of metformin to enhance the benefits of physical activity in healthy seniors. The findings suggest that metformin may "tame" the expectations of the drug as a treatment to extend healthspan when combined with exercise.
Source: Metformin Voids Benefits of Resistance Training
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