Abstract
BackgroundProfound skeletal muscle wasting and weakness is common after severe burn and persists for years after injury contributing to morbidity and mortality of burn patients. Currently, no ideal treatment exists to inhibit muscle catabolism. Metformin is an anti-diabetic agent that manages hyperglycemia but has also been shown to have a beneficial effect on stem cells after injury. We hypothesize that metformin administration will increase protein synthesis in the skeletal muscle by increasing the proliferation of muscle progenitor cells, thus mitigating muscle atrophy post-burn injury.MethodsTo determine whether metformin can attenuate muscle catabolism following burn injury, we utilized a 30% total burn surface area (TBSA) full-thickness scald burn in mice and compared burn injuries with and without metformin treatment. We examined the gastrocnemius muscle at 7 and 14 days post-burn injury.ResultsAt 7 days, burn injury significantly reduced myofiber cross-sectional area (CSA) compared to sham, p < 0.05. Metformin treatment significantly attenuated muscle catabolism and preserved muscle CSA at the sham size. To investigate metformin’s effect on satellite cells (muscle progenitors), we examined changes in Pax7, a transcription factor regulating the proliferation of muscle progenitors. Burned animals treated with metformin had a significant increase in Pax7 protein level and the number of Pax7-positive cells at 7 days post-burn, p < 0.05. Moreover, through BrdU proliferation assay, we show that metformin treatment increased the proliferation of satellite cells at 7 days post-burn injury, p < 0.05.ConclusionIn summary, metformin’s various metabolic effects and its modulation of stem cells make it an attractive alternative to mitigate burn-induced muscle wasting while also managing hyperglycemia.
Highlights
Burn injury results in a debilitating stress response termed the hypermetabolic response resulting in profound changes to several organ systems
Using a 30% total burn surface area (TBSA) murine burn model, we examined the effect of metformin treatment on mitigating burn-induced muscle wasting
Metformin treatment attenuates muscle wasting in mice To assess whether metformin attenuates muscle catabolism after severe burn injury, we examined animal weights, the dry/wet muscle ratio, and the cross-sectional muscle area
Summary
Burn injury results in a debilitating stress response termed the hypermetabolic response resulting in profound changes to several organ systems. With regard to skeletal muscle, metformin increases glucose uptake through upregulation of the glucose transporter type 4 (GLUT4) [14,15,16,17]. In addition to these effects, metformin activates the cellular energy sensor, AMP-activated protein kinase (AMPK) [17], which has a wide range of effects throughout the body in numerous organs which will be discussed in more detail later. We hypothesize that metformin administration will increase protein synthesis in the skeletal muscle by increasing the proliferation of muscle progenitor cells, mitigating muscle atrophy post-burn injury
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