The acute removal of metformin induces mitochondrial remodeling and increases mitochondrial respiration

Abstract

Metformin is a candidate to slow biological aging and extend healthspan, as it reduces the risk of morbidity and mortality in people with type 2 diabetes. However, it is not clear how metformin impacts individuals absent of chronic disease. This unknown is important to answer before prescribing metformin to healthy individuals to prolong the healthspan. It has been shown that metformin creates an inefficiency in energy transfer by accumulating within the mitochondria. Therefore, we hypothesized that the effects of metformin on healthspan are context specific; beneficial in the context of low energy demand/mitochondrial capacity but detrimental in the context of high energy demand/mitochondrial capacity. To test this hypothesis, we used 18-month, male rats selectively bred for low and high treadmill running capacity (LCR/HCR) as models of low and high intrinsic mitochondrial function. For both HCR and LCR, we used high-resolution respirometry (Oroboros O2K) on skeletal muscles from controls (CON), 4 weeks of metformin-treatment (MET), 4 weeks of metformin-treatment with a 48-hour metformin washout (MET-WO), and 48-hour washout with metformin added back to the respirometry chamber (MET-WO-SPIKE). A week prior to sacrifice, we labeled the rats with deuterium oxide to assess protein turnover as an indicator of mitochondrial remodeling. In gastrocnemius muscle, the HCR MET-WO had greater Complex I (CI), CI+Complex II (CII), and maximal respiration (MaxR) (115 ± 23, 164 ± 38, 157 ± 35 pmol/(s✕mg), respectively) compared to the CON (70 ± 24, p = 0.02, 114 ± 32, p = 0.01, 115 ± 40 pmol/(s✕mg), p = 0.04, respectively), and MET (63 ± 54, p = 0.007, 90 ± 50, p < 0.001, 91 ± 48 pmol/(s✕mg), p = 0.002, respectively). The HCR MET-SPIKE group had greater CII (83 ± 33 pmol/(s✕mg)) and MaxR (86 ± 35 pmol/(s✕mg)) compared to the MET (p = 0.007 and p = 0.002, respectively). In the soleus, MET-WO (4.15 ± 0.33%/day) had greater mitochondrial fractional synthesis rates (FSRs) compared to MET (3.12 ± 0.62%/day, p = 0.001) in the HCRs. In the LCRs, MET-WO (4.61 ± 0.42%/day) had greater FSRs compared to CON (p < 0.001, 3.07 ± 0.67%/day) and MET (3.12 ± 0.61%/day, p = 0.001). In the tibialis anterior, MET-WO (3.47 ± 0.80%/day) had greater FSRs compared to the MET (2.41 ± 0.47%/day, p = 0.04) within the HCRs with no differences in the LCR. These data show that metformin reduces mitochondrial respiration in HCR rats but not in LCR rats. The presence of metformin produced a greater subsequent response in HCR compared to LCR as shown by its acute removal revealing metformin-induced mitochondrial remodeling. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.