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. 2010 Dec 1;12(6):633-42.
doi: 10.1016/j.cmet.2010.11.008.

Total skeletal muscle PGC-1 deficiency uncouples mitochondrial derangements from fiber type determination and insulin sensitivity

Christoph Zechner  1 , Ling Lai, Juliet F Zechner, Tuoyu Geng, Zhen Yan, John W Rumsey, Deanna Collia, Zhouji Chen, David F Wozniak, Teresa C Leone, Daniel P Kelly
Affiliations

Total skeletal muscle PGC-1 deficiency uncouples mitochondrial derangements from fiber type determination and insulin sensitivity

Christoph Zechner et al. Cell Metab. .

Erratum in

  • Cell Metab. 2011 Jan 5;13(1):114

Abstract

Evidence is emerging that the PGC-1 coactivators serve a critical role in skeletal muscle metabolism, function, and disease. Mice with total PGC-1 deficiency in skeletal muscle (PGC-1α(-/-)β(f/f/MLC-Cre) mice) were generated and characterized. PGC-1α(-/-)β(f/f/MLC-Cre) mice exhibit a dramatic reduction in exercise performance compared to single PGC-1α- or PGC-1β-deficient mice and wild-type controls. The exercise phenotype of the PGC-1α(-/-)β(f/f/MLC-Cre) mice was associated with a marked diminution in muscle oxidative capacity, together with rapid depletion of muscle glycogen stores. In addition, the PGC-1α/β-deficient muscle exhibited mitochondrial structural derangements consistent with fusion/fission and biogenic defects. Surprisingly, the proportion of oxidative muscle fiber types (I, IIa) was not reduced in the PGC-1α(-/-)β(f/f/MLC-Cre) mice. Moreover, insulin sensitivity and glucose tolerance were not altered in the PGC-1α(-/-)β(f/f/MLC-Cre) mice. Taken together, we conclude that PGC-1 coactivators are necessary for the oxidative and mitochondrial programs of skeletal muscle but are dispensable for fundamental fiber type determination and insulin sensitivity.

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Figures

Figure 1
Figure 1. Global loss of PGC-1α combined with muscle-specific loss of PGC-1β results in a dramatic exercise performance deficit
2–3 month old male PGC-1βf/f (αβ+/+), PGC-1α−/−βf/f (α−/−), PGC-1βf/f/MLC-Cre (β−/−) and PGC-1α−/−βf/f/MLC-Cre (αβ−/−) mice were subjected to a run-to-exhaustion protocol on a motorized treadmill (n=6–7) as described in Experimental Procedures. Bars represent mean running time (+/− SEM) in minutes. * p < 0.05 vs. αβ+/+; ‡ p < 0.05 vs. α−/−; # p < 0.05 vs. β−/−. See also Figure S1.
Figure 2
Figure 2. PGC-1α−/−βf/f/MLC-Cre muscle exhibits an increase in myosin heavy chain (MHC) 1 positive fibers without a change in type II fiber distribution
(A) Cross-sections of gastrocnemius (Gastroc) muscle of 3–6 month old male PGC-1βf/f (αβ+/+), PGC-1α−/−βf/f (α−/−), PGC-1βf/f/MLC-Cre (β−/−) and PGC-1α−/−βf/f/MLC-Cre (αβ−/−) mice (n=5–6) stained for myosin I ATPase activity. Type I (MHC1 positive) fibers are stained dark. See also Figure S2. (B) (Top) Sections of plantaris muscle of 3–4 month old male mice (n=5–7) were immunostained for MHC1 (red), MHC2a (blue) and MHC2b (green). Representative images are shown. Scale bars denote 200 microns. (Bottom) Quantification results of the plantaris muscle MHC immunostaining studies expressed as mean percent (+/− SEM) of total muscle fibers. Unstained muscle fibers were counted as MHC2x positive. Insert shows magnification of MHC1 results. * p < 0.05 vs. αβ+/+; ‡ p < 0.05 vs. α−/−; # p < 0.05 vs. β−/−. (C) Succinate dehydrogenase (SDH) activity staining was performed on sections of gastrocnemius muscle (top row; n=5–6) and soleus muscle (bottom row; n=2) of 3–6 month old male mice of the indicated genotypes.
Figure 3
Figure 3. PGC-1α−/−βf/f/MCK-Cre muscle exhibits a mild increase in MHC1 positive fibers without a change in type II fiber formation
(A) Representative sections of GC and soleus muscle from PGC-1α−/−βf/f/MCK-Cre mice (see also Figure S3) stained for myosin ATPase activity. (B) Quantification of IHC immunostaining studies expressed as mean percent (+/− SEM) of total muscle fibers (n=3–5/group). * p < 0.05 vs. αβ+/+; ‡ p < 0.05 vs. α−/−; # p < 0.05 vs. β−/−.
Figure 4
Figure 4. PGC-1α and β drive an overlapping subset of target genes involved in mitochondrial processes
(A) Venn diagram displaying the results of gene expression microarray analysis conducted on RNA isolated from PGC-1α−/−βf/f (α−/−), PGC-1βf/f/MLC-Cre (β−/−), and PGC-1α−/−βf/f/MLC-Cre (αβ−/−) GC muscle compared to PGC-1βf/f controls. The numbers denote number of downregulated gene probes (≤0.7) in the corresponding sector. (B) Levels of mRNAs based on quantitative real-time RT-PCR performed on RNA isolated from GC muscle of 3–4 month old male mice from the genotypes indicated (n=8–10 per group). Abbreviations: citrate synthase (Cs), cytochrome c oxidase subunit 4 isoform 1 (Cox4i1), beta polypeptide of the H+ transporting mitochondrial F1 complex ATP synthase (Atp5b), adenine nucleotide translocator 1 (Ant1=Slc25a4), mitochondrial superoxide dismutase 2 (Sod2), the muscle isoform of carnitine-palmitoyl transferase 1 (Cpt1b), medium chain acyl-CoA dehydrogenase (Acadm), and nuclear respiratory factor 1 (Nrf1). Bars represent mean values (+/− SEM) normalized to 36B4 mRNA levels and expressed relative to PGC-1βf/f (αβ+/+) muscle (=1.0). * p < 0.05 vs. αβ+/+; ‡ p < 0.05 vs. α−/−; # p < 0.05 vs. β−/−.
Figure 5
Figure 5. PGC-1α−/−βf/f/MLC-Cre muscle exhibits mitochondrial structural and functional abnormalities and dysregulation of genes involved in mitochondrial dynamics
(A) Levels of mRNAs encoding mitochondrial fission and fusion genes including mitofusin 1 (Mfn1), mitofusin 2 (Mfn2), dynamin related protein 1 (Drp1 or dmn1l) and mitochondrial outer membrane fission 1 homolog (yeast) (Fis-1) determined by quantitative real-time RT-PCR (n=7–8 per group). Bars represent mean values (+/− SEM) normalized to 36B4 mRNA levels and expressed relative to PGC-1βf/f (αβ+/+) muscle (=1.0). (B) Representative electron micrographs of gastrocnemius showing subsarcolemmal mitochondria in sections from PGC-1α−/−βf/f mice (α−/−; top row) and PGC-1α−/−βf/f/MLC-Cre mice (middle row and magnified in bottom row). Note small, fragmented (white arrowhead) and elongated (black arrowhead) mitochondria. Scale bars represent 500nm. (C) Bars represent mean (+/− SEM) mitochondrial respiration rates determined on mitochondria isolated from the entire hindlimb muscle of the 4 genotypes shown using pyruvate or palmitoylcarnitine as a substrate (4–6 male animals per group). Rates were measured under the following conditions: basal, state 3 (ADP-stimulated), and post-oligomycin treatment (oligo-induced State 4). * p < 0.05 vs. αβ+/+; ‡ p < 0.05 vs. α−/−; # p < 0.05 vs. β−/−. See also Figure S4.
Figure 5
Figure 5. PGC-1α−/−βf/f/MLC-Cre muscle exhibits mitochondrial structural and functional abnormalities and dysregulation of genes involved in mitochondrial dynamics
(A) Levels of mRNAs encoding mitochondrial fission and fusion genes including mitofusin 1 (Mfn1), mitofusin 2 (Mfn2), dynamin related protein 1 (Drp1 or dmn1l) and mitochondrial outer membrane fission 1 homolog (yeast) (Fis-1) determined by quantitative real-time RT-PCR (n=7–8 per group). Bars represent mean values (+/− SEM) normalized to 36B4 mRNA levels and expressed relative to PGC-1βf/f (αβ+/+) muscle (=1.0). (B) Representative electron micrographs of gastrocnemius showing subsarcolemmal mitochondria in sections from PGC-1α−/−βf/f mice (α−/−; top row) and PGC-1α−/−βf/f/MLC-Cre mice (middle row and magnified in bottom row). Note small, fragmented (white arrowhead) and elongated (black arrowhead) mitochondria. Scale bars represent 500nm. (C) Bars represent mean (+/− SEM) mitochondrial respiration rates determined on mitochondria isolated from the entire hindlimb muscle of the 4 genotypes shown using pyruvate or palmitoylcarnitine as a substrate (4–6 male animals per group). Rates were measured under the following conditions: basal, state 3 (ADP-stimulated), and post-oligomycin treatment (oligo-induced State 4). * p < 0.05 vs. αβ+/+; ‡ p < 0.05 vs. α−/−; # p < 0.05 vs. β−/−. See also Figure S4.
Figure 6
Figure 6. Global loss of PGC-1α combined with muscle-specific loss of PGC-1β does not result in glucose intolerance or insulin resistance
(A) Mean blood glucose (+/− SEM) levels during GTT (left) and ITT (right) using 2–3 month old male littermate PGC-1βf/f (αβ+/+) and PGC-1βf/f/MLC-Cre (β−/−) mice on standard chow as described in Experimental Procedures (n=9–10). Total area under the glucose excursion curve (+/− SEM) is displayed in the inset for the GTT. (B) GTT and ITT results for 2–3 month old male littermate PGC-1α−/−βf/f (α−/−) and PGC-1α−/−βf/f/MLC-Cre (αβ−/−) mice on standard chow (n=11–13 per group). (C) Results of GTT (left) and ITT (right) conducted on 13 week old male mice after 8 weeks of high fat diet (n=3–6/group). See also Figure S5.
Figure 7
Figure 7. Combined loss of skeletal muscle PGC-1α and β results in rapid depletion of muscle glycogen during exercise
(A) Mean glycogen levels (+/− SEM) of GC muscle of sedentary 2–3 month old male mice of the indicated genotypes is shown on the left. The results of GC glycogen levels post-exercise are shown on the right. (B) Mean blood lactate levels (+/− SEM) at baseline (white bars) and following exhaustive exercise (black bars) for all 4 genotypes (n=5–10/group). (Run-to-exhaustion protocol described in text and “Experimental Procedures”). * p < 0.05 vs. αβ+/+; ‡ p < 0.05 vs. α−/−; # p < 0.05 vs. β−/−.
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