Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, C052

Oral Communications

The role of mitochondrial NDUFA4L2 in peripheral artery disease

Z. Liu1, M. Kalakoutis1, P. Tavi2,1, L. T. Johanna1

1. Karolinska Institutet, Stockholm, Sweden. 2. University of Eastern Finland, Kuopio, Finland.

Skeletal muscle weakness is part of the pathophysiology of peripheral artery disease (PAD), which is a common comorbidity in patients with obesity and type II diabetes. The molecular mechanism behind PAD-induced muscle weakness is not yet fully understood. Here we elucidate the role of the hypoxia-sensitive nuclear-encoded mitochondrial NDUFA4L2 protein in PAD-induced skeletal muscle weakness. To this purpose unilateral femoral artery ligation (FAL), a mouse model of PAD, was induced in C57BL6 mice on a normal chow diet (ND) and in C57BL6 mice that were kept on a high-fat diet (HFD) for eight weeks prior FAL. Anaesthesia was induced with 4% isoflurane prior to FAL and maintained with 2% isoflurane. All mice were sacrificed eight days post FAL by cervical disarticulation. In ND mice, NDUFA4L2 gene expression (t-test, p< 0.001, n=14) and protein expression (t-test, p< 0.01, n=11) were increased in quadriceps muscle from the FAL-leg as compared with the control leg (8 days post FAL). Moreover, the increase in NDUFA4L2 expression was associated with an ~50% reduction in muscle force production over a wide range of stimulation frequencies (20-120 Hz) in EDL and soleus muscle from the FAL leg as compared with the control leg (fold change=0.545, SE=0.072, p< 0.001, n=9-10 ). Both NDUFA4L2 protein and gene expression returned to baseline expression levels in muscle from the FAL-leg 30 days post FAL (n=6). The muscle force also returned to control levels 30 days post FAL (n=9). In HFD mice, the NDUFA4L2 gene expression and protein level was increased in the muscle from the FAL legs, yet the increase was significantly lower than in muscle from ND-FAL leg (8 days post FAL). Furthermore, the force production of EDL and soleus muscle from HFD-FAL legs were significantly lower than in the ND-FAL legs (EDL: fold change=0.013, SE=0.004, p<0.0001, n=6; soleus: fold change=0.120, SE=0.035, p<0.0001, n=6). Thus, the loss of force production was more severe in HFD-FAL muscle than in ND-FAL muscle. In conclusion, FAL induced NDUFA4L2 gene and protein expression that correlated with the loss of muscle force in EDL and soleus muscle. Eight weeks of HFD prior FAL attenuated the recovery of force loss in skeletal muscles, potentially through inhibiting the activation of NDUFA4L2. Thus, implicating NDUFA4L2 as an integral player in the remodelling process associated with FAL.

Where applicable, experiments conform with Society ethical requirements