Prolonged treatment with a PI3K p110α inhibitor causes sex- and tissue-dependent changes in antioxidant content, but does not affect mitochondrial function

Abstract Genetic inhibition of the p110α isoform of phosphatidylinositol-3-kinase (PI3K) can increase murine lifespan, enhance mitochondrial function and alter tissue-specific oxidative balance. Here, we investigated whether pharmacological inhibition of the p110α isoform of PI3K induces similar enhancement of mitochondrial function in middle-aged mice. Eight-month-old male and female mice were fed a diet containing 0.3 g/kg of the p110α-selective inhibitor BYL-719 (BYL) or a vehicle diet (VEH) for 6 weeks. Mice consuming BYL-719 had higher blood glucose and insulin, and tended towards decreased body weight. After 72 h, gene expression of the mitochondrial biogenesis mediators Pgc1α, Tfam and Nrf1 was greater in liver of BYL-719 males only, but unchanged in skeletal muscle of either sex. Six weeks of BYL-719 treatment did not affect mitochondrial content or function in the liver or skeletal muscle of either sex. In livers of males only, the expression of the antioxidant genes Nfe2l2, Cat, Sod1 and Sod2 increased within 72 h of BYL-719 treatment, and remained higher after 6 weeks. This was associated with an increase in hepatic GSH content and catalase protein expression, and lower H2O2 levels. Our results suggest that pharmacological inhibition of p110α in adult mice does not affect liver or skeletal muscle mitochondrial function, but does show sex- and tissue-specific effects on up-regulation of antioxidant response.

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The chicken skeletal muscle alpha-actin promoter is tissue specific in transgenic mice

Molecular and Cellular Biology ◽

10.1128/mcb.9.9.3785-3792.1989 ◽

1989 ◽

Vol 9 (9) ◽

pp. 3785-3792

Author(s):

C J Petropoulos ◽

M P Rosenberg ◽

N A Jenkins ◽

N G Copeland ◽

S H Hughes

Keyword(s):

Skeletal Muscle ◽

Transgenic Mice ◽

Striated Muscle ◽

Transcriptional Start Site ◽

Actin Gene ◽

Tissue Specific ◽

Adult Mice ◽

Transgenic Lines ◽

Alpha Actin ◽

Chicken Skeletal Muscle

We have generated transgenic mouse lines that carry the promoter region of the chicken skeletal muscle alpha (alpha sk) actin gene linked to the bacterial chloramphenicol acetyltransferase (CAT) gene. In adult mice, the pattern of transgene expression resembled that of the endogenous alpha sk actin gene. In most of the transgenic lines, high levels of CAT activity were detected in striated muscle (skeletal and cardiac) but not in the other tissues tested. In striated muscle, transcription of the transgene was initiated at the normal transcriptional start site of the chicken alpha sk actin gene. The region from nucleotides -191 to +27 of the chicken alpha sk actin gene was sufficient to direct the expression of CAT in striated muscle of transgenic mice. These observations suggest that the mechanism of tissue-specific actin gene expression is well conserved in higher vertebrate species.

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β-Hydroxybutyrate Elicits Favorable Mitochondrial Changes in Skeletal Muscle

International Journal of Molecular Sciences ◽

10.3390/ijms19082247 ◽

2018 ◽

Vol 19 (8) ◽

pp. 2247 ◽

Cited By ~ 8

Author(s):

Brian Parker ◽

Chase Walton ◽

Sheryl Carr ◽

Jacob Andrus ◽

Eric Cheung ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Cell ◽

Mitochondrial Function ◽

Mitochondrial Respiration ◽

Clinical Benefit ◽

Mitochondrial Fission ◽

Specific Effects ◽

General Improvement ◽

Neurological Conditions ◽

Insight Into

The clinical benefit of ketosis has historically and almost exclusively centered on neurological conditions, lending insight into how ketones alter mitochondrial function in neurons. However, there is a gap in our understanding of how ketones influence mitochondria within skeletal muscle cells. The purpose of this study was to elucidate the specific effects of β-hydroxybutyrate (β-HB) on muscle cell mitochondrial physiology. In addition to increased cell viability, murine myotubes displayed beneficial mitochondrial changes evident in reduced H2O2 emission and less mitochondrial fission, which may be a result of a β-HB-induced reduction in ceramides. Furthermore, muscle from rats in sustained ketosis similarly produced less H2O2 despite an increase in mitochondrial respiration and no apparent change in mitochondrial quantity. In sum, these results indicate a general improvement in muscle cell mitochondrial function when β-HB is provided as a fuel.

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The chicken skeletal muscle alpha-actin promoter is tissue specific in transgenic mice.

Molecular and Cellular Biology ◽

10.1128/mcb.9.9.3785 ◽

1989 ◽

Vol 9 (9) ◽

pp. 3785-3792 ◽

Cited By ~ 36

Author(s):

C J Petropoulos ◽

M P Rosenberg ◽

N A Jenkins ◽

N G Copeland ◽

S H Hughes

Keyword(s):

Skeletal Muscle ◽

Transgenic Mice ◽

Striated Muscle ◽

Transcriptional Start Site ◽

Actin Gene ◽

Tissue Specific ◽

Adult Mice ◽

Transgenic Lines ◽

Alpha Actin ◽

Chicken Skeletal Muscle

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Impact of 17β-estradiol on complex I kinetics and H2O2 production in liver and skeletal muscle mitochondria

Journal of Biological Chemistry ◽

10.1074/jbc.ra118.005148 ◽

2018 ◽

Vol 293 (43) ◽

pp. 16889-16898 ◽

Cited By ~ 13

Author(s):

Maria J. Torres ◽

Terence E. Ryan ◽

Chien-Te Lin ◽

Tonya N. Zeczycki ◽

P. Darrell Neufer

Keyword(s):

Skeletal Muscle ◽

Complex I ◽

Molecular Mechanisms ◽

Liver Mitochondria ◽

H2o2 Production ◽

Tissue Specific ◽

Muscle Mitochondria ◽

Specific Effects ◽

Skeletal Muscle Mitochondria ◽

17Β Estradiol

Naturally or surgically induced postmenopausal women are widely prescribed estrogen therapies to alleviate symptoms associated with estrogen loss and to lower the subsequent risk of developing metabolic diseases, including diabetes and nonalcoholic fatty liver disease. However, the molecular mechanisms by which estrogens modulate metabolism across tissues remain ill-defined. We have previously reported that 17β-estradiol (E2) exerts antidiabetogenic effects in ovariectomized (OVX) mice by protecting mitochondrial and cellular redox function in skeletal muscle. The liver is another key tissue for glucose homeostasis and a target of E2 therapy. Thus, in the present study we determined the effects of acute loss of ovarian E2 and E2 administration on liver mitochondria. In contrast to skeletal muscle mitochondria, E2 depletion via OVX did not alter liver mitochondrial respiratory function or complex I (CI) specific activities (NADH oxidation, quinone reduction, and H2O2 production). Surprisingly, in vivo E2 replacement therapy and in vitro E2 exposure induced tissue-specific effects on both CI activity and on the rate and topology of CI H2O2 production. Overall, E2 therapy protected and restored the OVX-induced reduction in CI activity in skeletal muscle, whereas in liver mitochondria E2 increased CI H2O2 production and decreased ADP-stimulated respiratory capacity. These results offer novel insights into the tissue-specific effects of E2 on mitochondrial function.

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Tissue-specific dysregulation of mitochondrial respiratory capacity and coupling control in colon-26 tumor-induced cachexia

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00028.2019 ◽

2019 ◽

Vol 317 (1) ◽

pp. R68-R82 ◽

Cited By ~ 9

Author(s):

Jessica L. Halle ◽

Gabriel S. Pena ◽

Hector G. Paez ◽

Adrianna J. Castro ◽

Harry B. Rossiter ◽

...

Keyword(s):

Skeletal Muscle ◽

Weight Loss ◽

Mitochondrial Function ◽

Cancer Cachexia ◽

Systemic Disease ◽

Respiratory Capacity ◽

Tissue Specific ◽

Colon 26 ◽

Specific Control ◽

Mitochondrial Respiratory

In addition to skeletal muscle dysfunction, cancer cachexia is a systemic disease involving remodeling of nonmuscle organs such as adipose and liver. Impairment of mitochondrial function is associated with multiple chronic diseases. The tissue-specific control of mitochondrial function in cancer cachexia is not well defined. This study determined mitochondrial respiratory capacity and coupling control of skeletal muscle, white adipose tissue (WAT), and liver in colon-26 (C26) tumor-induced cachexia. Tissues were collected from PBS-injected weight-stable mice, C26 weight-stable mice and C26 mice with moderate (10% weight loss) and severe cachexia (20% weight loss). The respiratory control ratio [(RCR) an index of oxidative phosphorylation (OXPHOS) coupling efficiency] was low in WAT during the induction of cachexia because of high nonphosphorylating LEAK respiration. Liver RCR was low in C26 weight-stable and moderately cachexic mice because of reduced OXPHOS. Liver RCR was further reduced with severe cachexia, where Ant2 but not Ucp2 expression was increased. Ant2 was inversely correlated with RCR in the liver ( r = −0.547, P < 0.01). Liver cardiolipin increased in moderate and severe cachexia, suggesting this early event may also contribute to mitochondrial uncoupling. Impaired skeletal muscle mitochondrial respiration occurred predominantly in severe cachexia, at complex I. These findings suggest that mitochondrial function is subject to tissue-specific control during cancer cachexia, whereby remodeling in WAT and liver arise early and may contribute to altered energy balance, followed by impaired skeletal muscle respiration. We highlight an under-recognized role of liver and WAT mitochondrial function in cancer cachexia and suggest mitochondrial function of multiple tissues to be therapeutic targets.

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Linking bioenergetic function of mitochondria to tissue-specific molecular fingerprints

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00088.2019 ◽

2019 ◽

Vol 317 (2) ◽

pp. E374-E387 ◽

Cited By ~ 10

Author(s):

Lisa Kappler ◽

Miriam Hoene ◽

Chunxiu Hu ◽

Christine von Toerne ◽

Jia Li ◽

...

Keyword(s):

Skeletal Muscle ◽

Mitochondrial Function ◽

Complex I ◽

Mitochondrial Protein ◽

Liver Mitochondria ◽

Quinone Oxidoreductase ◽

Molecular Fingerprints ◽

Consistent Finding ◽

Tissue Specific ◽

Muscle Mitochondria

Mitochondria are dynamic organelles with diverse functions in tissues such as liver and skeletal muscle. To unravel the mitochondrial contribution to tissue-specific physiology, we performed a systematic comparison of the mitochondrial proteome and lipidome of mice and assessed the consequences hereof for respiration. Liver and skeletal muscle mitochondrial protein composition was studied by data-independent ultra-high-performance (UHP)LC-MS/MS-proteomics, and lipid profiles were compared by UHPLC-MS/MS lipidomics. Mitochondrial function was investigated by high-resolution respirometry in samples from mice and humans. Enzymes of pyruvate oxidation as well as several subunits of complex I, III, and ATP synthase were more abundant in muscle mitochondria. Muscle mitochondria were enriched in cardiolipins associated with higher oxidative phosphorylation capacity and flexibility, in particular CL(18:2)4 and 22:6-containing cardiolipins. In contrast, protein equipment of liver mitochondria indicated a shuttling of complex I substrates toward gluconeogenesis and ketogenesis and a higher preference for electron transfer via the flavoprotein quinone oxidoreductase pathway. Concordantly, muscle and liver mitochondria showed distinct respiratory substrate preferences. Muscle respired significantly more on the complex I substrates pyruvate and glutamate, whereas in liver maximal respiration was supported by complex II substrate succinate. This was a consistent finding in mouse liver and skeletal muscle mitochondria and human samples. Muscle mitochondria are tailored to produce ATP with a high capacity for complex I-linked substrates. Liver mitochondria are more connected to biosynthetic pathways, preferring fatty acids and succinate for oxidation. The physiologic diversity of mitochondria may help to understand tissue-specific disease pathologies and to develop therapies targeting mitochondrial function.

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Tissue-specific dysregulation of mitochondrial respiratory capacity and coupling control in colon-26 tumor-induced cachexia

10.1101/493056 ◽

2018 ◽

Author(s):

Andy V Khamoui ◽

Jessica L Halle ◽

Gabriel S Pena ◽

Hector G Paez ◽

Harry B Rossiter ◽

...

Keyword(s):

Skeletal Muscle ◽

Weight Loss ◽

Mitochondrial Function ◽

Cancer Cachexia ◽

Systemic Disease ◽

Respiratory Capacity ◽

Tissue Specific ◽

Colon 26 ◽

Specific Control ◽

Mitochondrial Respiratory

In addition to skeletal muscle dysfunction, recent frameworks describe cancer cachexia as a systemic disease involving remodeling of non-muscle organs such as adipose and liver. Impairment of mitochondrial function is associated with multiple diseases. The tissue-specific control of mitochondrial function in cancer cachexia is not well-defined. This study determined mitochondrial respiratory capacity and coupling control of skeletal muscle, white adipose tissue (WAT), and liver in colon-26 (C26) tumor-induced cachexia. Tissues were collected from PBS-injected weight-stable mice, C26 mice that were weight-stable, and C26 mice with moderate (10% weight loss) and severe cachexia (20% weight loss). WAT showed high non-phosphorylating LEAK respiration and reduced respiratory control ratio (RCR, index of OXPHOS coupling efficiency) during the induction of cachexia. Liver RCR decreased early due to cancer, and further declined with severe cachexia, where Ant2 but not Ucp2 expression was increased. Ant2 also related inversely with RCR in the liver (r=-0.547, p<0.01), suggesting a role for Ant2 in uncoupling of liver OXPHOS. Increased liver cardiolipin occurred during moderate cachexia and remained elevated in severe cachexia, suggesting this early event may also contribute to uncoupling. Impaired skeletal muscle mitochondrial respiration occurred predominantly in severe cachexia. These findings suggest that mitochondrial function is subject to tissue-specific control during cancer cachexia, whereby remodeling in WAT and liver arise early and could contribute to altered energy balance, followed by impaired skeletal muscle respiration. We highlight an underrecognized role of liver mitochondria in cancer cachexia, and suggest mitochondrial function of multiple tissues to be targets for therapeutic intervention.

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