Perturbations in the network of nuclear and mitochondrial factors controlling mitochondrial functions, also consisting of morphogenesis machinery proteins and metabolic sensors, may produce mitochondrial dysfunction and metabolic inflexibility. Indeed, high fat diet (HFD)-induced impairment of lipid oxidation in skeletal muscle (SKM) mitochondria can lead to accumulation of intramyocellular lipid (IMCL) and subsequent altered insulin signalling and reduced glucose uptake.

3,5-diiodo-L-thyronine (T2) administration to HFD-fed rats exerts a systemic hypolipidemic effect and produces, at the muscle level, a lack of: IMCL accumulation, insulin resistance, and slow oxidative fiber enrichment.

Here, we deeper characterized the response of SKM metabolism to T2 (4-weeks administration to HFD rats) focusing on mitochondrial proteomes and functions.

In line with the glycolytic phenotype of gastrocnemius muscle of HFD-T2-treated rats, T2 determined a down-regulation of enzymes involved in intra-mitochondrial oxidative metabolism, stimulated the activity of respiratory complex I, IV and V, enhanced heavier respiratory supercomplexes, likely advantaging the respirosome, and induced a more efficient utilization of carbohydrates. Moreover, T2 prevented HFD-induced over expression of key factors of mitochondrial biogenesis (PGC 1a and PGC 1b) as well as down-regulation of proteins involved in mitochondrial fusion, (mitofusin 2) known to be positively correlated with glucose utilization and insulin-sensitivity.

The obtained data further prove that T2 counteracts HFD-induced structural/metabolic alterations in SKM producing important effects on mitochondria simultaneously affecting energy efficiency, glucose metabolism and ROS production.