A PGC-1α Isoform Induced by Resistance Training Regulates Skeletal Muscle Hypertrophy

Department of Cell Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. Electronic address: .
Cell (Impact Factor: 33.12). 12/2012; 151(6):1319-31. DOI: 10.1016/j.cell.2012.10.050
Source: PubMed

ABSTRACT PGC-1α is a transcriptional coactivator induced by exercise that gives muscle many of the best known adaptations to endurance-type exercise but has no effects on muscle strength or hypertrophy. We have identified a form of PGC-1α (PGC-1α4) that results from alternative promoter usage and splicing of the primary transcript. PGC-1α4 is highly expressed in exercised muscle but does not regulate most known PGC-1α targets such as the mitochondrial OXPHOS genes. Rather, it specifically induces IGF1 and represses myostatin, and expression of PGC-1α4 in vitro and in vivo induces robust skeletal muscle hypertrophy. Importantly, mice with skeletal muscle-specific transgenic expression of PGC-1α4 show increased muscle mass and strength and dramatic resistance to the muscle wasting of cancer cachexia. Expression of PGC-1α4 is preferentially induced in mouse and human muscle during resistance exercise. These studies identify a PGC-1α protein that regulates and coordinates factors involved in skeletal muscle hypertrophy.

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    • "Activation of IGF1-Akt/PKB triggers hypertrophy , while its suppression determines muscle atrophy (Schiaffino and Mammucari, 2011). In addition, IGF1-Akt/PKB signaling is activated by PGC-1a4 (Ruas et al., 2012). Accordingly , Akt was phosphorylated, and thus activated, by AAV- MCU (Figure 3M). "
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    ABSTRACT: Muscle atrophy contributes to the poor prognosis of many pathophysiological conditions, but pharmacological therapies are still limited. Muscle activity leads to major swings in mitochondrial [Ca(2+)], which control aerobic metabolism, cell death, and survival pathways. We investigated in vivo the effects of mitochondrial Ca(2+) homeostasis in skeletal muscle function and trophism by overexpressing or silencing the mitochondrial calcium uniporter (MCU). The results demonstrate that in both developing and adult muscles, MCU-dependent mitochondrial Ca(2+) uptake has a marked trophic effect that does not depend on aerobic control but impinges on two major hypertrophic pathways of skeletal muscle, PGC-1α4 and IGF1-Akt/PKB. In addition, MCU overexpression protects from denervation-induced atrophy. These data reveal a novel Ca(2+)-dependent organelle-to-nucleus signaling route that links mitochondrial function to the control of muscle mass and may represent a possible pharmacological target in conditions of muscle loss. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 03/2015; 10(8):1269-79. DOI:10.1016/j.celrep.2015.01.056 · 8.36 Impact Factor
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    • "NT-PGC-1í µí»¼-a Enhances Mitochondrial Oxidative Function in C 2 C 12 Myotube Cells. A recent study reported a muscle-specific PGC-1í µí»¼ isoform, PGC-1í µí»¼4, which has shown to be induced by resistance training [17]. PGC-1í µí»¼4 is actually identical to NT-PGC-1í µí»¼-b, which is derived from exon 1b of the PGC-1í µí»¼ gene. "
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    ABSTRACT: PGC-1α is an inducible transcriptional coactivator that regulates mitochondrial biogenesis and cellular energy metabolism in skeletal muscle. Recent studies have identified two additional PGC-1α transcripts that are derived from an alternative exon 1 (exon 1b) and induced by exercise. Given that the PGC-1α gene also produces NT-PGC-1α transcript by alternative 3(') splicing between exon 6 and exon 7, we have investigated isoform-specific expression of NT-PGC-1α mRNA in mouse skeletal muscle during physical exercise with different intensities. We report here that NT-PGC-1α-a mRNA expression derived from a canonical exon 1 (exon 1a) is increased by high-intensity exercise and AMPK activator AICAR in mouse skeletal muscle but not altered by low- and medium-intensity exercise and β 2-adrenergic receptor agonist clenbuterol. In contrast, the alternative exon 1b-driven NT-PGC-1α-b (PGC-1α4) and NT-PGC-1α-c are highly induced by low-, medium-, and high-intensity exercise, AICAR, and clenbuterol. Ectopic expression of NT-PGC-1α-a in C2C12 myotube cells upregulates myosin heavy chain (MHC I, MHC II a) and Glut4, which represent oxidative fibers, and promotes the expression of mitochondrial genes (Cyc1, COX5B, and ATP5B). In line with gene expression data, citrate synthase activity was significantly increased by NT-PGC-1α-a in C2C12 myotube cells. Our results indicate the regulatory role for NT-PGC-1α-a in mitochondrial biogenesis and adaptation of skeletal muscle to endurance exercise.
    BioMed Research International 07/2014; 2014:402175. DOI:10.1155/2014/402175 · 2.71 Impact Factor
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    • "Identification of METRNL as a Key PGC-1a4 Target Gene in Skeletal Muscle We utilized two independent and unbiased approaches to identify secreted factors controlled by PGC1a4 that might contribute to the browning of white fat: gene expression analyses combined with bioinformatics algorithms and quantitative mass spectrometry of secreted proteins. First, we screened affymetrix data obtained upon PGC1a4 overexpression in primary myotubes (Ruas et al., 2012) to identify potential candidates that satisfied all of the following criteria (1) >2-fold change in mRNA expression, (2) presence of an N-terminal signal peptide, and (3) absence of a transmembrane domain. The fold change of short-listed genes was independently confirmed in the quadriceps muscle from Myo-PGC-1a4 mice by qPCR (list of the short-listed genes, Table S1). "
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    ABSTRACT: Exercise training benefits many organ systems and offers protection against metabolic disorders such as obesity and diabetes. Using the recently identified isoform of PGC1-α (PGC1-α4) as a discovery tool, we report the identification of meteorin-like (Metrnl), a circulating factor that is induced in muscle after exercise and in adipose tissue upon cold exposure. Increasing circulating levels of Metrnl stimulates energy expenditure and improves glucose tolerance and the expression of genes associated with beige fat thermogenesis and anti-inflammatory cytokines. Metrnl stimulates an eosinophil-dependent increase in IL-4 expression and promotes alternative activation of adipose tissue macrophages, which are required for the increased expression of the thermogenic and anti-inflammatory gene programs in fat. Importantly, blocking Metrnl actions in vivo significantly attenuates chronic cold-exposure-induced alternative macrophage activation and thermogenic gene responses. Thus, Metrnl links host-adaptive responses to the regulation of energy homeostasis and tissue inflammation and has therapeutic potential for metabolic and inflammatory diseases.
    Cell 06/2014; 157(6):1279-1291. DOI:10.1016/j.cell.2014.03.065 · 33.12 Impact Factor
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