The effects of the transcriptional coactivators PGC-1alpha and PGC-1beta on muscle metabolism and insulin sensitivity
Zusammenfassung der Projektergebnisse
Both PGC-1α and PGC-1β are transcriptional coactivators that have been suggested by a plethora of gain-of function studies in cell culture and in animal models to play key roles in skeletal muscle fiber type determination, mitochondrial biogenesis and the expression of enzymes involved in energy metabolism. In contrast to the dramatic effects observed in overexpression studies, lack of either PGC- 1α or PGC-1β in muscle as well as other tissues results in rather moderate phenotypes. We examined the hypothesis that skeletal muscle PGC-1α and PGC-1β compensate for the loss of each other, thus preserving skeletal muscle function. We examined this hypothesis in mice that lack PGC-1β in skeletal muscle on top of a global lack of PGC-1α (“PGC-1αβ-/- mice”). Mice were viable and appeared grossly normal. While mice with global loss of PGC-1α or mice with skeletal muscle-specific loss of PGC-1β demonstrated a mild performance deficit when exercised on a treadmill at low intensity, PGC-1αβ-/- mice demonstrated a dramatic exercise performance deficit. Vigorous evaluation of the phenotype of PGC-1αβ-/- mice was performed. Surprisingly, mice deficient in both PGC-1α and β did not demonstrate a switch to “faster” myosin heavy chain (MHC) isoforms as would have been suggested by previous studies suggesting a major role of PGC-1 in slow MHC fiber type determination. These results provide evidence that physiological levels of PGC-1α and β transcriptional coactivators are not necessary for the formation of MHC1 positive muscle fibers. Close examination of mitochondria by electron microscopy revealed elongated groups of mitochondria. Mitochondrial DNA in PGC-1αβ-/- mice was downregulated, indicating decreased mitochondrial copy number. The activity of the enzyme succinate dehydrogenase (SDH) was found to be mildly reduced in both PGC-1α-/- and PGC-1β-/- muscle but dramatically reduced in PGC-1αβ-/- muscle, indicating a major compromise in mitochondrial function only when both PGC-1 isoforms are lost. DNA microarray analyses revealed that almost one quarter (22.3%) of analyzed genes in the mitochondrial gene ontology pathway “mitochondrion” were downregulated only in PGC-1αβ-/- muscle but not in PGC-1α-/- or PGC-1β-/- muscle. These findings support the concept that the transcriptional coactivators PGC-1α and PGC-1β compensate for each other in skeletal muscle in vivo in the regulation of muscle mitochondrial functional capacity and glucose metabolism.
Projektbezogene Publikationen (Auswahl)
- Research Seminar - Prof. Dr. med. Torsten Doenst, Heisenberg-Professor, Department for Cardiac Surgery, University of Leipzig Heart Center, Leipzig, Germany: “Der Verlust von PGC-1β bewirkt eine Verminderung der körperlichen Leistungsfähigkeit, ultrastrukturelle Veränderungen und mitochondriale Dysfunktion im Skelettmuskel"
- "A Role for the Transcriptional Coactivator PGC-1α in Muscle Refueling", J Biol Chem, 282 (50): 36642-36651, 2007
Wende AR, Schaeffer PJ, Parker GJ, Zechner C, Han DH, Chen MM, Hancock CR, Huss JM, McClain DA, Holloszy JO, and Kelly DP
- "Loss of PGC-1β Results in Reduced Exercise Performance, Ultrastructural Alterations and Mitochondrial Dysfunction in Skeletal Muscle" Diabetologia 50:Suppl1:0175 (2007)
Zechner C, Lai L, Leone TC, Schaeffer PJ, Kelly DP
- "The Transcriptional Coactivators PGC-1α and PGC-1β Control Overlapping Programs Required for Postnatal Cardiac Function and Survival", Genes & Dev, 22 (14): 1948-1961, 2008
Lai L, Zechner C, Leone TC, Schaeffer PJ, Kelly SM, Flanagan DP, Medeiros DM, Saffitz JE, Kovacs A, and Kelly DP
- “Transcriptional Coactivators PGC-1α and PGC-1β Control Overlapping Programs Required for Cardiac Mitochondrial Maturation”, Circ Res 103:e56-P108 (2008)
Lai L, Zechner C, Leone TC, Schaeffer PJ, Kelly SM, Flanagan DP, Medeiros DM, Kovacs A, and Kelly DP
