Abstract
In previous studies, we have characterized a new hormonal pathway involving a mitochondrial T3 receptor (p43) acting as a mitochondrial transcription factor and consequently stimulating mitochondrial activity and mitochondrial biogenesis. We have established the involvement of this T3 pathway in the regulation of in vitro myoblast differentiation.We have generated mice overexpressing p43 under control of the human α-skeletal actin promoter. In agreement with the previous characterization of this promoter, northern-blot and western-blot experiments confirmed that after birth p43 was specifically overexpressed in skeletal muscle. As expected from in vitro studies, in 2-month old mice, p43 overexpression increased mitochondrial genes expression and mitochondrial biogenesis as attested by the increase of mitochondrial mass and mt-DNA copy number. In addition, transgenic mice had a body temperature 0.8°C higher than control ones and displayed lower plasma triiodothyronine levels. Skeletal muscles of transgenic mice were redder than wild-type animals suggesting an increased oxidative metabolism. In line with this observation, in gastrocnemius, we recorded a strong increase in cytochrome oxidase activity and in mitochondrial respiration. Moreover, we observed that p43 drives the formation of oxidative fibers: in soleus muscle, where MyHC IIa fibers were partly replaced by type I fibers; in gastrocnemius muscle, we found an increase in MyHC IIa and IIx expression associated with a reduction in the number of glycolytic fibers type IIb. In addition, we found that PGC-1α and PPARδ, two major regulators of muscle phenotype were up regulated in p43 transgenic mice suggesting that these proteins could be downstream targets of mitochondrial activity. These data indicate that the direct mitochondrial T3 pathway is deeply involved in the acquisition of contractile and metabolic features of muscle fibers in particular by regulating PGC-1α and PPARδ.
Highlights
Skeletal muscle of vertebrates contain myofibers differing in contractile function, mitochondrial content and metabolic properties
Production of p43 overexpressing mice In order to assess the importance of p43 in the control of muscle fiber plasticity and of mitochondrial biogenesis, we have generated mice overexpressing this mitochondrial T3 receptor under control of the 2.2-kb human a-skeletal actin promoter (HSA) flanked by chicken b-globin 59HS4 insulator (Figure 1A)
Relative to MyHC gene expression and mitochondrial activity, skeletal muscle of p43 overexpressing mice displays more oxidative and slow muscle fibers: in soleus muscle, MyHC IIa were partly replaced by type I fibers, and in gastrocnemius muscle, we found an increase in MyHC IIa and IIx fibers associated with a reduction of type IIb glycolytic fibers
Summary
Skeletal muscle of vertebrates contain myofibers differing in contractile function, mitochondrial content and metabolic properties. Fast-twitch fibers express type II MHCs including three subtypes: IIa, IIx and IIb. Type IIb fibers display a reduced mitochondrial density associated with a principally glycolytic metabolism. In addition to its metabolic activity, triiodothyronine (T3) affects developmental processes, and is in particular considered as a major regulator of in vivo muscle development. This hormone stimulates growth of this tissue by increasing the number and diameter of muscle fibers [3,4], and regulates the transition between neonatal and adult myosin isoforms [5] and influences the contractile features of adult muscle fibers [6]. These receptors are ligand-dependent transcription factors that constituvely bind to specific sequences called thyroid hormone response elements (T3RE) located in the promoter of T3 target genes
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