Detrimental Effects of Metformin on Mitochondrial Function in Healthy Rats

Objectives: Diabetes causes mitochondrial dysfunction representing an important pathomechanism in the development of heart failure and affecting surgical outcome. Metformin is a first-line treatment in diabetic and heart failure, confers a survival benefit under certain stress conditions and is recommended for use in cardiac surgery. However, it is not clear how Metformin influences mitochondrial function. We thus investigated mitochondrial function in different organs in a model of diabetes (high fat diet fed rats) and compared it to healthy controls fed normal chow and to assess the influence of Metformin treatment.

Methods: Animals were fed normal chow (NC) or high fat diet (HFD). At three weeks of age, metformin treatment (300 mg/kg/d) was started. At the age of 13 weeks, cardiac, skeletal muscle and liver mitochondria were isolated. Mitochondrial function was determined by citrate synthase and respiratory capacity.

Results: HFD led to an increase in body weight and impaired glucose tolerance. Metformin reversed these effects. HFD induced an increase in citrate synthase activity in heart (143 ± 12 vs. 164 ± 12 U/mg heart weight) and skeletal muscle but a decrease in liver. In addition, HFD reduced mitochondrial respiratory capacity with complex I (heart: pyruvate/malate 495 ± 53 vs. 315 ± 21 natomsO/min/mg protein), complexes II, III, and IV substrates in cardiac and skeletal muscle mitochondria.

In HFD fed animals, metformin treatment reversed the decline in citrate synthase activity and mitochondrial respiratory capacity in heart (glutamate/malate: 378 ± 45 vs. 557 ± 52) and skeletal muscle (succinate/rot: 240 ± 25 vs. 302 ± 43). Surprisingly, metformin treatment in animals fed normal chow led to reduced citrate synthase activity (M. soleus: 62.6 ± 8.7 vs. 35.7 ± 5.7 U/mg M. soleus weight) in skeletal muscle. Furthermore, mitochondrial respiratory capacity was impaired with complex I (liver: glutamate 114 ± 6 vs. 79 ± 4 natomsO/min/mg protein), II (M. gastrocnemius: succinate/rotenone 363 ± 52 vs. 254 ± 30 natomsO/min/mg protein), III (heart: DHQ 1,443 ± 189 vs. 917 ± 67 natomsO/min/mg protein), and complex IV substrates (M. gastrocnemius: TMPD 1 003 ± 142 vs. 634 ± 70) in heart, skeletal muscle and liver.

Conclusion: Metformin appears to protect mitochondrial function at times of metabolic stress (e.g., high fat diet). However, under normal conditions, it may even be detrimental. This finding suggests a potential value for metformin use in cardiac surgery but only for diabetic patients.