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Metformin attenuates skeletal muscle transcriptional and mitochondrial respiratory adaptations to aerobic exercise training.

ABSTRACT: We have previously demonstrated that the inhibitory effect of metformin on skeletal muscle complex-I linked mitochondrial respiration was associated with attenuated improvements in whole-body insulin sensitivity and cardiorespiratory fitness after aerobic exercise training (AET) in older adults. However, the mechanism(s) by which metformin impacts skeletal muscle adaptations to aerobic exercise remains unclear. To understand potential mechanisms associated with the inhibitory effect of metformin on mitochondrial adaptations to AET, we evaluated the skeletal muscle transcriptome, mitochondrial respiration, and hydrogen peroxide (H2O2) emissions in 7-month-old male C57BL6/J mice after 8-weeks of non-exercise sedentary control (SED) or progressive AET with and without metformin treatment. Metformin attenuated the number of differentially expressed genes by AET (975 vs. 449). Pathway analysis suggests that metformin suppressed several signal transduction pathways involved in oxidative capacity and cellular metabolism, including VEGF, AMPK, HIF-1α, and PI3K-AKT. Notably, the addition of metformin to AET suppressed 16 downstream targets of HIF-1α and was accompanied by metformin ameliorating the increase in mitochondrial respiratory capacity and ADP sensitivity after AET. However, neither AET nor AET+MET impacted mitochondrial H2O2 emitting potential. Given the central role of HIF-1α as an upstream transcriptional regulator of mitochondrial function and biogenesis, these results suggest that suppression of HIF-1α pathway by metformin could serve as a transcriptional regulatory node associated with the inhibitory role of metformin on skeletal muscle mitochondrial adaptations to aerobic exercise training.

ORGANISM(S): Mus musculus

PROVIDER: GSE287490 | GEO | 2025/03/03

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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Metformin attenuates skeletal muscle transcriptional and mitochondrial respiratory adaptations to aerobic exercise training.

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