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PGC-1α isoform heterodimerization restricts transcription factor docking and limits metabolic adaptations in skeletal muscle

ABSTRACT: The PGC-1a gene is expressed as several transcriptional coactivator variants that regulate numerous adaptive processes. These include thermogenesis, hepatic metabolism, neuroprotection, and skeletal muscle adaptation to exercise training. To support such diverse functions, PGC-1 isoform expression and activation are under tight tissue- and context-specific control. Notably, PGC-1 isoforms generated by alternative gene promoter usage, and splicing are highly induced in skeletal muscle upon exercise. Here we show that PGC-12 and 3 are PGC-11 dimerization partners that limit its activity. Skeletal muscle PGC-12 and PGC-13 transgenics have reduced exercise performance and strength, which partially overlaps with PGC-1 loss-of-function. Mechanistically, PGC-11/3 dimerization precludes ERR recruitment and coactivation, so their co-expression in skeletal muscle impairs the innate bioenergetic adaptations characteristic of PGC-11 transgenics and reduces oxidative metabolism gene expression and exercise capacity. Removing this break to PGC-1a1 activity may have therapeutic applications in metabolic diseases and increase responsiveness to training.

ORGANISM(S): Mus musculus

PROVIDER: GSE203299 | GEO | 2022/05/21

REPOSITORIES: GEO

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Project description:Title: Total Skeletal Muscle PGC-1 Deficiency Uncouples Mitochondrial Derangements from Fiber Type Determination and Insulin Sensitivity 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-/- βf/f/MLC-Cre mice) were generated and characterized. PGC-1α-/-βf/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-/-βf/f/MLC-Cre mice was associated with a marked diminution in muscle oxidative capacity and mitochondrial structural derangements consistent with fusion/fission and biogenic defects together with rapid depletion of muscle glycogen stores during exercise. Surprisingly, the skeletal muscle fiber type profile of the PGC-1α-/-βf/f/MLCCre mice was not significantly different than the wild-type mice. Moreover, insulin sensitivity and glucose tolerance were also not altered in the PGC-1α-/-βf/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. RNA from PGC-1alpha-/- beta f/f/Mlc1fcre was obtained and gene expression pattern compared with PGC-1alpha -/-, PGC-1beta f/f, and PGC-1beta f/f/Mlc1fCre controls. Results file descriptions: 1. GSE23365_skfloxAKO_PPexcl_genesup_GEO-8-16-2010: This table contains genes that were upregulated ≥2.0 fold in gastrocnemius muscle from PGC-1alpha-/- - mice, PGC-1beta f/f/Mlc1fCre mice and PGC-1alpha-/- - beta f/f/Mlc1fCre mice. All groups are normalized to PGC-1beta f/f mice and values are expressed as mean±SEM. The column “description’ contains the gene name, and the column “ID” contains Agilent probe names. 2. GSE23365_skfloxAKO_PPexcl_genesdown_GEO-8-16-2010 This table contains genes that were downregulated ≤0.7 fold in gastrocnemius muscle from PGC-1alpha-/- - mice, PGC-1beta f/f/Mlc1fCre mice and PGC-1alpha-/- - beta f/f/Mlc1fCre mice. All groups are normalized to PGC-1beta f/f mice and values are expressed as mean±SEM. The column “description’ contains the gene name, and the column “ID” contains Agilent probe names.

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PGC-1α isoform heterodimerization restricts transcription factor docking and limits metabolic adaptations in skeletal muscle

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