Abstract
PGC-1α regulates critical processes in muscle physiology, including mitochondrial biogenesis, lipid metabolism and angiogenesis. Furthermore, PGC-1α was suggested as an important regulator of fiber type determination. However, whether a muscle fiber type-specific PGC-1α content exists, whether PGC-1α content relates to basal levels of mitochondrial content, and whether such relationships are preserved between humans and classically used rodent models are all questions that have been either poorly addressed or never investigated. To address these issues, we investigated the fiber type-specific content of PGC-1α and its relationship to basal mitochondrial content in mouse, rat and human muscles using in situ immunolabeling and histochemical methods on muscle serial cross-sections. Whereas type IIa fibers exhibited the highest PGC-1α in all three species, other fiber types displayed a hierarchy of type IIx>I>IIb in mouse, type I = IIx> IIb in rat, and type IIx>I in human. In terms of mitochondrial content, we observed a hierarchy of IIa>IIx>I>IIb in mouse, IIa >I>IIx> IIb in rat, and I>IIa> IIx in human skeletal muscle. We also found in rat skeletal muscle that type I fibers displayed the highest capillarization followed by type IIa >IIx>IIb. Finally, we found in human skeletal muscle that type I fibers display the highest lipid content, followed by type IIa>IIx. Altogether, our results reveal that (i) the fiber type-specific PGC-1α and mitochondrial contents were only matched in mouse, (ii) the patterns of PGC-1α and mitochondrial contents observed in mice and rats do not correspond to that seen in humans in several respects, and (iii) the classical phenotypes thought to be regulated by PGC-1α do not vary exclusively as a function of PGC-1α content in rat and human muscles.
Highlights
PGC-1a is a coactivator of transcription involved in multiple aspects of skeletal muscle physiology
Specificity of the PGC-1a antibody To ensure the specificity of our PGC-1a antibody, we first determined PGC-1a content in homogenates of mouse gastrocnemius muscle, rat soleus and plantaris muscles, human vastus lateralis muscle and in a mixture of skeletal muscles obtained from PGC-1a knock out mice
While no band was observed for samples from PGC-1a knock out mice, it is important to note that the amount of proteins loaded for PGC-1a knock out mice was much higher as compared to the amount of proteins loaded for the gastrocnemius of wild type mice
Summary
PGC-1a is a coactivator of transcription involved in multiple aspects of skeletal muscle physiology. Muscle-specific overexpression of PGC-1a results in the activation of genes regulating mitochondrial oxidative metabolism [1] and increases mitochondrial content in both cardiac and skeletal muscles [2,3,4,5]. Muscle-specific Knock Out (MKO) of PGC-1a was shown to reduce mitochondrial gene expression and mitochondrial content in mouse skeletal muscle [6]. In PGC-1a MKO mice it was recently shown that PGC-1a plays a critical role in endurance traininginduced mitochondrial biogenesis [7], this latter finding has been recently challenged [8]. In addition to controlling mitochondrial biogenesis, PGC-1a plays a crucial role in the regulation of angiogenesis where musclespecific overexpression of PGC-1a was shown to increase the capillary density in mouse skeletal muscle [9]. Muscle-specific overexpression of PGC-1a speeds the recovery of muscle blood flow following the ligation and ablation of the femoral artery, while muscle blood flow recovery is severely blunted in PGC-1a2/2 animals following the same surgery [9]
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