The microRNA miR-696 regulates PGC-1α in mouse skeletal muscle in response to physical activity

Aoi, Wataru; Naito, Yuji; Mizushima, Katsura; Takanami, Yoichi; Kawai, Yukari; Ichikawa, Hiroshi; Yoshikawa, Toshikazu

doi:10.1152/ajpendo.00448.2009

Cited by 174 publications

(142 citation statements)

References 52 publications

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“…This suggests that inhibition of PARP activities is beneficial to promote skeletal muscle energy expenditure. One promising strategy to inhibit the activity of endogenous PARPs would be modulation of the miRNA-mediated pathway, which plays a key role in skeletal muscle metabolism (22,(29)(30)(31)(32)(33). To achieve this, we attempted to identify miRNAs that control PARP expression.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-149 Inhibits PARP-2 and Promotes Mitochondrial Biogenesis via SIRT-1/PGC-1α Network in Skeletal Muscle

et al. 2014

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High-fat diet (HFD) plays a central role in the initiation of mitochondrial dysfunction that significantly contributes to skeletal muscle metabolic disorders in obesity. However, the mechanism by which HFD weakens skeletal muscle metabolism by altering mitochondrial function and biogenesis is unknown. Given the emerging roles of microRNAs (miRNAs) in the regulation of skeletal muscle metabolism, we sought to determine whether activation of a specific miRNA pathway would rescue the HFD-induced mitochondrial dysfunction via the sirtuin-1 (SIRT-1)/ peroxisome proliferator–activated receptor γ coactivator-1α (PGC-1α) pathway, a pathway that governs genes necessary for mitochondrial function. We here report that miR-149 strongly controls SIRT-1 expression and activity. Interestingly, miR-149 inhibits poly(ADP-ribose) polymerase-2 (PARP-2) and so increased cellular NAD+ levels and SIRT-1 activity that subsequently increases mitochondrial function and biogenesis via PGC-1α activation. In addition, skeletal muscles from HFD-fed obese mice exhibit low levels of miR-149 and high levels of PARP-2, and they show reduced mitochondrial function and biogenesis due to a decreased activation of the SIRT-1/PGC-1α pathway, suggesting that mitochondrial dysfunction in the skeletal muscle of obese mice may be because of, at least in part, miR-149 dysregulation. Overall, miR-149 may be therapeutically useful for treating HFD-induced skeletal muscle metabolic disorders in such pathophysiological conditions as obesity and type 2 diabetes.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-149 Inhibits PARP-2 and Promotes Mitochondrial Biogenesis via SIRT-1/PGC-1α Network in Skeletal Muscle

et al. 2014

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“…MiR-696 negatively regulates expression of PGC-1a protein 12 and Western blots indicated that all anti-miR treatments significantly increased PGC-1a protein expression compared to negative control (Fig. 1C, D).…”

Section: Microrna Inhibition In 2d Cultures Accelerates Myogenesis Anmentioning

confidence: 89%

“…38 Aoi et al found that levels of PPARGC1A were unchanged for miR-696 overexpression and inhibition. 12 Likewise, in 2D and 3D culture, PPARG-C1A expression was unchanged following miR-133a and miR-696 inhibition. Results are consistent with miR-133a and miR-696 inhibiting the initiation of PGC-1a translation.…”

Section: Fig 5 Isometric Force Testing Of Muscle Bundles (A)mentioning

confidence: 94%

“…Aoi et al identified stretch-sensitive miR-696, which regulates the expression of an important and potent metabolism coactivator, PGC-1a, and observed heightened levels of PGC-1a protein levels in anti-miR-696 C2C12 samples 24 h after transfection. 12 Heightened expression of PGC-1a, which is encoded by the gene PPARGC1A, 13 has been linked to increased oxidative energy metabolism and type I (slow twitch) myofiber formation. [13][14][15] Recently, we extended our results with murine C2C12 cells and showed that transient inhibition of miR-133a alone accelerated myogenesis in two-dimensional cultures of primary human myoblasts.…”

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confidence: 99%

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Cell Density and Joint microRNA-133a and microRNA-696 Inhibition Enhance Differentiation and Contractile Function of Engineered Human Skeletal Muscle Tissues

Cheng

Ran

Bursac

et al. 2016

Tissue Engineering Part A

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To utilize three-dimensional (3D) engineered human skeletal muscle tissue for translational studies and in vitro studies of drug toxicity, there is a need to promote differentiation and functional behavior. In this study, we identified conditions to promote contraction of engineered human skeletal muscle bundles and examined the effects of transient inhibition of microRNAs (miRs) on myogenic differentiation and function of two-dimensional (2D) and 3D cultures of human myotubes. In 2D cultures, simultaneously inhibiting both miR-133a, which promotes myoblast proliferation, and miR-696, which represses oxidative metabolism, resulted in an increase in sarcomeric a-actinin protein and the metabolic coactivator PGC-1a protein compared to transfection with a scrambled miR sequence (negative control). Although PGC-1a was elevated following joint inhibition of miRs 133a and 696, there was no difference in myosin heavy chain (MHC) protein isoforms. 3D engineered human skeletal muscle myobundles seeded with 5 · 10 6 human skeletal myoblasts (HSkM)/mL and cultured for 2 weeks after onset of differentiation consistently did not contract when stimulated electrically, whereas those seeded with myoblasts at 10 · 10 6 HSkM/mL or higher did contract. When HSkM were transfected with both anti-miRs and seeded into fibrin hydrogels and cultured for 2 weeks under static conditions, twitch and tetanic specific forces after electrical stimulation were greater than for myobundles prepared with HSkM transfected with scrambled sequences. Immunofluorescence and Western blots of 3D myobundles indicate that anti-miR-133a or anti-miR-696 treatment led to modest increases in slow MHC, but no consistent increase in fast MHC. Similar to results in 2D, only myobundles prepared with myoblasts treated with anti-miR-133a and anti-miR-696 produced an increase in PGC-1a mRNA. PGC-1a targets were differentially affected by the treatment. HIF-2a mRNA showed an expression pattern similar to that of PGC-1a mRNA, but COXII mRNA levels were not affected by the anti-miRs. Overall, joint inhibition of miR-133a and miR-696 accelerated differentiation, elevated the metabolic coactivator PGC-1a, and increased the contractile force in 3D engineered human skeletal muscle bundles.

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“…1). Interestingly, all of these miRNAs are regulated by exercise (16)(17)(18). Since both exercise and caloric restriction are linked to increased SIRT-1 activity and improved mitochondrial function, it will be interesting to investigate whether miR-149, and by extension also PARP-2, is differentially regulated in these metabolically beneficial states.…”

mentioning

confidence: 99%

MicroRNAs Emerge as Modulators of NAD+-Dependent Energy Metabolism in Skeletal Muscle

Svensson

Handschin

2014

Diabetes

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Obesity, type 2 diabetes, and related metabolic disorders are associated with reduced mitochondrial function in skeletal muscle and other organs (1). However, causality of aberrant mitochondrial activity in the etiology of these diseases and the exact mechanism(s) linking metabolic pathologies to mitochondrial dysfunction are still under debate. Therefore, a better molecular understanding of this observation is required in order to design novel therapeutic strategies aimed at modulation of mitochondrial function in these disease contexts. The silent mating type information regulation 2 homolog 1 (SIRT-1) and the peroxisome proliferator-activated receptor g coactivators 1 (PGC-1) are important regulators of mitochondrial function in skeletal muscle (1). In response to deacetylation by SIRT-1, PGC-1a is activated and subsequently promotes an oxidative muscle fiber phenotype. In turn, SIRT-1 activity is regulated by the substrate NAD + , and thus acts as an intracellular rheostat by increasing mitochondrial biogenesis to match the energy needs of the cell (2).Interestingly, recent studies have exploited this mechanism by using the NAD + precursors nicotinamide riboside (3) and nicotinamide mononucleotide (4) to increase SIRT-1 activity and thereby the oxidative capacity of skeletal muscle. Alternatively, intracellular NAD + can be elevated through inhibition of other enzymes that use NAD + . In particular, the poly(ADP-ribose) polymerases (PARPs), which metabolize NAD + to form polymers of ADP-ribose (PAR) on other proteins, are major consumers of NAD + in various cell types. PARPs are involved in regulation of several distinct cellular processes, such as DNA repair, inflammation, and differentiation (5), but they have also recently been recognized as having important roles in metabolism (6). In fact, germ-line deletion of either PARP-1 or PARP-2, or pharmacological inhibition of PARP activity by PJ-34, results in elevated intracellular NAD + levels in skeletal muscle with the expected outcome of increased SIRT-1 activity and mitochondrial oxidative function (7,8). In most tissues, PARP-1 accounts for the vast majority (.85%) of cellular PARP activity, and is therefore also the major NAD + consumer (6). Thus, PARP-1 deletion presumably affects SIRT-1 primarily due to increased NAD + levels (8). In contrast, even though PARP-2 null mice also show increased NAD + levels (7), PARP-2 also acts as a transcriptional repressor of SIRT-1 (7).Modulation of PARP activity provides a novel therapeutic strategy to increase SIRT-1 expression and activity in skeletal muscle, and represents an alternative to pharmacological activation of SIRT-1 using resveratrol or SRT1720 (9,10). Interestingly, several studies indicate that PARP activity in murine skeletal muscle is dysregulated during high-fat diet (HFD) feeding (8) and aging (11), implying a direct involvement of PARPs in development of metabolic dysfunction in muscle. This idea is now further supported in the study by Mohamed et al. (12) published in this issue, in which the ...

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The microRNA miR-696 regulates PGC-1α in mouse skeletal muscle in response to physical activity

Cited by 174 publications

References 52 publications

MicroRNA-149 Inhibits PARP-2 and Promotes Mitochondrial Biogenesis via SIRT-1/PGC-1α Network in Skeletal Muscle

MicroRNA-149 Inhibits PARP-2 and Promotes Mitochondrial Biogenesis via SIRT-1/PGC-1α Network in Skeletal Muscle

Cell Density and Joint microRNA-133a and microRNA-696 Inhibition Enhance Differentiation and Contractile Function of Engineered Human Skeletal Muscle Tissues

MicroRNAs Emerge as Modulators of NAD+-Dependent Energy Metabolism in Skeletal Muscle

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