Abstract
Hyperlipidemic state-associated perturbations in the network of factors controlling mitochondrial functions, i. e., morphogenesis machinery and metabolic sensor proteins, produce metabolic inflexibility, insulin resistance and reduced oxidative capacity in skeletal muscle. Moreover, intramyocellular lipid (IMCL) accumulation leads to tissue damage and inflammation. The administration of the naturally occurring metabolite 3,5-diiodo-L-thyronine (T2) with thyromimetic actions to high fat diet (HFD)-fed rats exerts a systemic hypolipidemic effect, which produces a lack of IMCL accumulation, a shift toward glycolytic fibers and amelioration of insulin sensitivity in gastrocnemius muscle. In this study, an integrated approach combining large-scale expression profile and functional analyses was used to characterize the response of skeletal muscle mitochondria to T2 during a HFD regimen. Long-term T2 administration to HDF rats induced a glycolytic phenotype of gastrocnemius muscle as well as an adaptation of mitochondria to the fiber type, with a decreased representation of enzymes involved in mitochondrial oxidative metabolism. At the same time, T2 stimulated the activity of individual respiratory complex I, IV, and V. Moreover, T2 prevented the HFD-associated increase in the expression of peroxisome proliferative activated receptor γ coactivator-1α and dynamin-1-like protein as well as mitochondrial morphological aberrations, favoring the appearance of tubular and tethered organelles in the intermyofibrillar regions. Remarkably, T2 reverted the HDF-associated expression pattern of proinflammatory factors, such as p65 subunit of NF-kB, and increased the fiber-specific immunoreactivity of adipose differentiation–related protein in lipid droplets. All together, these results further support a role of T2 in counteracting in vivo some of the HFD-induced impairment in structural/metabolic features of skeletal muscle by impacting the mitochondrial phenotype.
Highlights
Skeletal muscle is a key node in the powerful and complex cross-talk between metabolically active tissues in maintaining energy homeostasis
To gain insights into the effects exerted by HFD and T2treatment on mitochondrial phenotype, solubilized proteins from gastrocnemius muscle mitochondria of N, HFD, and HFD+T2 rats were subjected to a 2D-E-based proteomic analysis
After T2-treatment, all the lipid droplets were intensely Adipocyte Differentiation-Related Protein (ADRP) immunostained both in fast/glycolytic and slow/oxidative fibers (Figure 7B), indicating differential and opposing effects of HFD and T2-treatment on the ADRP-dependent control of lipid storage. While it has well-established that high-fat feeding impairs insulin-stimulated glucose transport and uptake rates (Hansen et al, 1998; Tremblay et al, 2001; Krisan et al, 2004; Yaspelkis et al, 2007), the causative role of mitochondria dysfunction in this impairment remains not clearly elucidated
Summary
Skeletal muscle is a key node in the powerful and complex cross-talk between metabolically active tissues in maintaining energy homeostasis. In the highly regulated molecular network controlling the formation of muscle fibers, coordinating mitochondrial biogenesis and affecting metabolic capabilities of pre-existing mitochondria, a central role is played by peroxisome proliferative activated receptor γ coactivator-1α (PGC-1α). This transcriptional coactivator is generally considered to act as a master regulator of the energy management of skeletal muscle fibers (Lin et al, 2002; Lagouge et al, 2006)
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