Gene expression-based screening identifies microtubule inhibitors as inducers of PGC-1α and oxidative phosphorylation

Arany, Zoltàn; Wagner, Bridget K.; Ma, Yue; Chinsomboon, Jessica; Laznik, Dina; Spiegelman, Bruce M.

doi:10.1073/pnas.0800979105

Cited by 80 publications

(62 citation statements)

References 42 publications

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“…From a mechanistic perspective SIRT1 has also been shown to enhance insulin sensitivity in insulin-resistant myotubes via repression of the protein-tyrosine phosphatase 1B (37). Recently, small molecule activators of PGC-1␣ itself has been described (38). These compounds need to be explored as alternative agents to modify this program in skeletal muscle and to evaluate whether they too can restore insulin signaling.…”

Section: Discussionmentioning

confidence: 99%

PGC-1α Integrates Insulin Signaling, Mitochondrial Regulation, and Bioenergetic Function in Skeletal Muscle

Pagel-Langenickel¹,

Bao²,

Joseph³

et al. 2008

Journal of Biological Chemistry

109

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The pathophysiology underlying mitochondrial dysfunction in insulin-resistant skeletal muscle is incompletely characterized. To further delineate this we investigated the interaction between insulin signaling, mitochondrial regulation, and function in C2C12 myotubes and in skeletal muscle. In myotubes elevated insulin and glucose disrupt insulin signaling, mitochondrial biogenesis, and mitochondrial bioenergetics. The insulin-sensitizing thiazolidinedione pioglitazone restores these perturbations in parallel with induction of the mitochondrial biogenesis regulator PGC-1␣. Overexpression of PGC-1␣ rescues insulin signaling and mitochondrial bioenergetics, and its silencing concordantly disrupts insulin signaling and mitochondrial bioenergetics. In primary skeletal myoblasts pioglitazone also up-regulates PGC-1␣ expression and restores the insulin-resistant mitochondrial bioenergetic profile. In parallel, pioglitazone upregulates PGC-1␣ in db/db mouse skeletal muscle. Interestingly, the small interfering RNA knockdown of the insulin receptor in C2C12 myotubes down-regulates PGC-1␣ and attenuates mitochondrial bioenergetics. Concordantly, mitochondrial bioenergetics are blunted in insulin receptor knock-out mouse-derived skeletal myoblasts. Taken together these data demonstrate that elevated glucose and insulin impairs and pioglitazone restores skeletal myotube insulin signaling, mitochondrial regulation, and bioenergetics. Pioglitazone functions in part via the induction of PGC-1␣. Moreover, PGC-1␣ is identified as a bidirectional regulatory link integrating insulin-signaling and mitochondrial homeostasis in skeletal muscle.Understanding the pathophysiology initiating the development of insulin resistance should augment our capacity to identify novel therapeutic targets for the prevention and treatment of type 2 diabetes. This biology remains incompletely characterized in part due to the complexity of the interaction of multiple organ systems and the multiplicity of intracellular perturbations within these organs governing the development of insulin resistance. The major peripheral organ systems implicated in insulin resistance include skeletal muscle, adipose tissue, liver, and the immune system. The enhancement of our understanding of this biology will require the combination of reductionist and systems biological approaches.The complexity of the effects of insulin resistance in a single organ is exemplified in skeletal muscle where disruption in glucose uptake (1), insulin signaling (2, 3), glycogen synthesis (4) and in mitochondrial biology (5-7) are evident in insulin-resistant subjects up to two decades before their developing diabetes. A fundamental question arising is whether disruption of skeletal muscle mitochondria is a primary component in this disease pathophysiology or whether it is a consequence of reduced aerobic activity in response to alternate metabolic perturbations associated with insulin resistance and diabetes (8). Although this question has not been definitively answered, increasing mitocho...

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Section: Discussionmentioning

confidence: 99%

PGC-1α Integrates Insulin Signaling, Mitochondrial Regulation, and Bioenergetic Function in Skeletal Muscle

Pagel-Langenickel¹,

Bao²,

Joseph³

et al. 2008

Journal of Biological Chemistry

109

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“…This screening technique demonstrated that PGC-1␣ expression can be regulated by microtubule and protein synthesis inhibitors (Arany et al, 2008). Although these compounds do not harbor significant therapeutic potential, the technique demonstrates the ability to screen for inducers of PGC-1␣, and screening larger libraries may ultimately provide new useful inducers of PGC-1␣.…”

mentioning

confidence: 99%

“…Spiegelman and colleagues recently developed a quantitative PCR screen to identify inducers of PGC-1␣ expression (Arany et al, 2008). This screening technique demonstrated that PGC-1␣ expression can be regulated by microtubule and protein synthesis inhibitors (Arany et al, 2008).…”

mentioning

confidence: 99%

5-Hydroxytryptamine Receptor Stimulation of Mitochondrial Biogenesis

Rasbach

Funk²,

Jayavelu³

et al. 2009

J Pharmacol Exp Ther

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Mitochondrial dysfunction is both a cause and target of reactive oxygen species during ischemia-reperfusion, drug, and toxicant injury. After injury, renal proximal tubular cells (RPTC) recover mitochondrial function by increasing the expression of the master regulator of mitochondrial biogenesis, peroxisomeproliferator-activated-receptor-␥-coactivator-1␣ (PGC-1␣). The goal of this study was to determine whether 5-hydroxytryptamine (5-HT) receptor agonists increase mitochondrial biogenesis and accelerate the recovery of mitochondrial function. -193). In addition, DOI accelerated the recovery of mitochondrial function after oxidant-induced injury in RPTC. This is the first report to demonstrate 5-HT receptor-mediated mitochondrial biogenesis, and we suggest that 5-HT-agonists may be effective in the treatment of mitochondrial and cell injury.

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“…Mixed results have been obtained with the fibrate drug bezafibrate, a pan-peroxisome proliferator-activated receptor agonist (Wenz et al, 2008;Romanino et al, 2011;Yatsuga and Suomalainen, 2012). A recent high-throughput screen in murine primary skeletal muscle cells elucidated several distinct classes of drugs promoting MB; however, several of these, including glucocorticoids and inhibitors of microtubules and protein synthesis, would not be suitable for clinical administration due to toxicity and side effects (Arany et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Agonism of the 5-Hydroxytryptamine 1F Receptor Promotes Mitochondrial Biogenesis and Recovery from Acute Kidney Injury

Garrett¹,

Whitaker²,

Beeson³

et al. 2014

J Pharmacol Exp Ther

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Many acute and chronic conditions, such as acute kidney injury, chronic kidney disease, heart failure, and liver disease, involve mitochondrial dysfunction. Although we have provided evidence that drug-induced stimulation of mitochondrial biogenesis (MB) accelerates mitochondrial and cellular repair, leading to recovery of organ function, only a limited number of chemicals have been identified that induce MB. The goal of this study was to assess the role of the 5-hydroxytryptamine 1F (5-HT 1F ) receptor in MB. Immunoblot and quantitative polymerase chain reaction analyses revealed 5-HT 1F receptor expression in renal proximal tubule cells (RPTC). A MB screening assay demonstrated that two selective 5-HT 1F receptor agonists, LY334370 (4-fluoro-N-[3-(1-methyl-4-piperidinyl)-1H-indol-5-yl]benzamide) and LY344864 (N-[(3R)-3-(dimethylamino)-2,3,4,9-tetrahydro-1H-carbazol-6-yl]-4-fluorobenzamide; 1-100 nM) increased carbonylcyanide-ptrifluoromethoxyphenylhydrazone-uncoupled oxygen consumption in RPTC, and validation studies confirmed both agonists increased mitochondrial proteins [e.g., ATP synthase b, cytochrome c oxidase 1 (Cox1), and NADH dehydrogenase (ubiquinone) 1b subcomplex subunit 8 (NDUFB8)] in vitro. Small interfering RNA knockdown of the 5-HT 1F receptor blocked agonistinduced MB. Furthermore, LY344864 increased peroxisome proliferator-activated receptor coactivator 1-a, Cox1, and NDUFB8 transcript levels and mitochondrial DNA (mtDNA) copy number in murine renal cortex, heart, and liver. Finally, LY344864 accelerated recovery of renal function, as indicated by decreased blood urea nitrogen and kidney injury molecule 1 and increased mtDNA copy number following ischemia/reperfusion-induced acute kidney injury (AKI). In summary, these studies reveal that the 5-HT 1F receptor is linked to MB, 5-HT 1F receptor agonism promotes MB in vitro and in vivo, and 5-HT 1F receptor agonism promotes recovery from AKI injury. Induction of MB through 5-HT 1F receptor agonism represents a new target and approach to treat mitochondrial organ dysfunction.

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Gene expression-based screening identifies microtubule inhibitors as inducers of PGC-1α and oxidative phosphorylation

Cited by 80 publications

References 42 publications

PGC-1α Integrates Insulin Signaling, Mitochondrial Regulation, and Bioenergetic Function in Skeletal Muscle

PGC-1α Integrates Insulin Signaling, Mitochondrial Regulation, and Bioenergetic Function in Skeletal Muscle

5-Hydroxytryptamine Receptor Stimulation of Mitochondrial Biogenesis

Agonism of the 5-Hydroxytryptamine 1F Receptor Promotes Mitochondrial Biogenesis and Recovery from Acute Kidney Injury

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