Mitochondrial biogenesis in striated muscles: rapid induction of citrate synthase mRNA by nerve stimulation

1991 ◽  
Vol 260 (2) ◽  
pp. C266-C270 ◽  
Author(s):  
B. H. Annex ◽  
W. E. Kraus ◽  
G. L. Dohm ◽  
R. S. Williams
Keyword(s):  
Mitochondrial Biogenesis ◽  
Nerve Stimulation ◽  
Time Course ◽  
Citrate Synthase ◽  
Contractile Activity ◽  
Cdna Probe ◽  
Nuclear Gene ◽  
Mitochondrial Genes ◽  
Adult Rabbit ◽  
Mitochondrial Rna

Tonic contractile activity induces mitochondrial biogenesis in mammalian skeletal muscles, necessitating regulation of both nuclear and mitochondrial genes encoding mitochondrial proteins. In this study we compared the time course of induction of citrate synthase (CS) mRNA, a nuclear gene product, to that of genes encoded by mitochondrial DNA during the adaptive response to indirect nerve stimulation in tibialis anterior muscles of adult rabbits. A CS cDNA probe was prepared from a rabbit heart cDNA library by the polymerase chain reaction using synthetic oligonucleotide primers based on the published sequence of the porcine gene. This cDNA probe hybridized to a single band on Northern blots of total or polyadenylated RNA from adult rabbit tissues. Nerve stimulation for 3 days increased the abundance of CS mRNA relative to total cellular RNA by 2.3 +/- 0.2-fold (mean +/- SE, n = 8; P less than 0.01). In contrast, CS enzyme activity and mitochondrial RNA transcripts were not significantly increased at this time point. However, when nerve stimulation was continued for 21 days, the increases in CS mRNA and mitochondrial RNAs were similar. These results support the hypothesis that genetic signaling mechanisms triggered by neural input are sensed initially within the nucleus and that expression of mitochondrial genes is regulated as a secondary event.

RNA subunit of mitochondrial RNA-processing enzyme is induced by contractile activity in striated muscle

1993 ◽  
Vol 265 (6) ◽  
pp. C1511-C1516 ◽  
Author(s):  
G. A. Ordway ◽  
K. Li ◽  
G. A. Hand ◽  
R. S. Williams
Keyword(s):  
Mitochondrial Biogenesis ◽  
Nerve Stimulation ◽  
Small Rna ◽  
Rna Processing ◽  
Skeletal Muscles ◽  
Citrate Synthase ◽  
Contractile Activity ◽  
Regulatory Function ◽  
Mitochondrial Rna ◽  
Mtdna Replication

A small RNA encoded within the nucleus of yeast and mammalian cells is an essential subunit of a mitochondrial RNA-processing endonuclease (RNase MRP) that generates primers for mitochondrial DNA (mtDNA) replication. We examined expression of MRP-RNA in specialized subtypes of mammalian striated muscles that differ markedly in respiratory activity and in muscles subjected to chronic stimulation via the motor nerve, a potent stimulus to mitochondrial biogenesis. MRP-RNA was more abundant in mitochondria-rich cardiac and slow-twitch skeletal muscles than in glycolytic fast-twitch skeletal muscles. Forced contractile activity resulting from nerve stimulation increased expression of MRP-RNA by 3.5-fold within the first day and by 14-fold within 14 days. Changes in abundance of MRP-RNA preceded but otherwise occurred in parallel to changes in specific activity of citrate synthase, a marker of mitochondrial proliferation shown previously to correlate with mtDNA copy number in this model. Another small RNA (U1) also was induced transiently (1-3 days) by nerve stimulation, but such changes were not sustained and were of less magnitude (< 4-fold) than changes in MRP-RNA. These findings are consistent with the hypothesis that MRP-RNA may have a regulatory function with respect to mtDNA replication and mitochondrial biogenesis.

Induction of a fast-oxidative phenotype by chronic muscle stimulation: histochemical and metabolic studies

1996 ◽  
Vol 270 (1) ◽  
pp. C313-C320 ◽  
Author(s):  
C. N. Mayne ◽  
H. Sutherland ◽  
J. C. Jarvis ◽  
S. J. Gilroy ◽  
A. J. Craven ◽  
...  
Keyword(s):  
Time Course ◽  
Citrate Synthase ◽  
Fiber Type ◽  
Adult Rabbit ◽  
Myosin Isoforms ◽  
Two Phase ◽  
Coa Transferase ◽  
Oxidative Phenotype ◽  
Aggregate Amount

Chronic electrical stimulation of skeletal muscle at 10 Hz induces fast-to-slow fiber type transformation. Does a lower aggregate amount of activity lead to a less complete transformation, or does it produce the same transformation over a longer time course? We examined this question by subjecting adult rabbit tibialis anterior and extensor digitorum longus muscles to continuous stimulation at 2.5 Hz for 2-12 wk. Most of the fibers acquired the histochemical and immunocytochemical characteristics of type 2A, not type 1, fibers. There was a corresponding rise in oxidative activity, but this was accompanied by a marked decline in anaerobic glycolysis. The activities of hexokinase and 3-oxoacid CoA-transferase stopped increasing after 2 wk, glutamate oxaloacetate transaminase after 4 wk, and beta-hydroxyacyl-CoA dehydrogenase after 6 wk of stimulation. Succinate dehydrogenase, citrate synthase, lactate dehydrogenase, and creatine phosphokinase continued to change up to 12 wk of stimulation. Changes in enzyme activity were not as rapid or as marked as those observed for stimulation at 10 Hz, and none showed the typical two-phase response of oxidative enzyme activities to stimulation at 10 Hz. The latter may therefore be dependent on induction of type 1 myosin isoforms.

Effects of inhibition of mitochondrial protein synthesis in skeletal muscle

1987 ◽  
Vol 253 (6) ◽  
pp. C866-C871 ◽  
Author(s):  
R. S. Williams ◽  
W. Harlan
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Adaptive Response ◽  
Citrate Synthase ◽  
Contractile Activity ◽  
Mitochondrial Protein ◽  
Mitochondrial Genes ◽  
Mitochondrial Protein Synthesis ◽  
Inhibit Activity ◽  
Genes Encoding

To evaluate the participation of proteins derived from mitochondrial genes in the adaptive response of skeletal muscle to increased contractile activity, we administered chloramphenicol (CAP; 200-1,000 mg.kg-1.day-1), an inhibitor of translation from mitochondrial ribosomes, to adult rabbits undergoing electrical stimulation of the tibialis anterior muscle of one hind limb. In unmedicated animals, 10 days of electrical stimulation increased maximum velocity (Vmax) of cytochrome oxidase and citrate synthase by 214 +/- 17 and 201 +/- 16% (P less than 0.01). In a dose-dependent manner, CAP abolished activity-induced increases in cytochrome oxidase Vmax, suggesting that augmented mitochondrial protein synthesis is necessary for the adaptive response of enzymes that require protein subunits encoded by mitochondrial genes. However, CAP failed to inhibit activity-induced changes in Vmax of enzymes derived exclusively from nuclear genes (citrate synthase and aldolase). CAP also failed to inhibit activity-induced increases in mRNA transcribed from the nuclear genes encoding beta-F1 ATPase or myoglobin, or from the mitochondrial genes encoding 12S rRNA, 16S rRNA, or cytochrome b. These latter findings suggest that mitochondrial translation products do not participate in pretranslational regulation of these nuclear or mitochondrial genes in response to changes in contractile activity of skeletal muscle.

Schisandrin Restores the Amyloid β-Induced Impairments on Mitochondrial Function, Energy Metabolism, Biogenesis, and Dynamics in Rat Primary Hippocampal Neurons

Pharmacology ◽  
2021 ◽  
pp. 1-11
Author(s):  
Zhongyuan Piao ◽  
Lin Song ◽  
Lifen Yao ◽  
Limei Zhang ◽  
Yichan Lu
Keyword(s):  
Energy Metabolism ◽  
Cytochrome C ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Function ◽  
Hippocampal Neurons ◽  
Citrate Synthase ◽  
Mitochondrial Permeability Transition ◽  
Amyloid Β ◽  
Mitochondrial Functions ◽  
Primary Hippocampal Neurons

Introduction: Schisandrin which is derived from Schisandra chinensis has shown multiple pharmacological effects on various diseases including Alzheimer’s disease (AD). It is demonstrated that mitochondrial dysfunction plays an essential role in the pathogenesis of neurodegenerative disorders. Objective: Our study aims to investigate the effects of schisandrin on mitochondrial functions and metabolisms in primary hippocampal neurons. Methods: In our study, rat primary hippocampal neurons were isolated and treated with indicated dose of amyloid β1–42 (Aβ1–42) oligomer to establish a cell model of AD in vitro. Schisandrin (2 μg/mL) was further subjected to test its effects on mitochondrial function, energy metabolism, mitochondrial biogenesis, and dynamics in the Aβ1–42 oligomer-treated neurons. Results and Conclusions: Our findings indicated that schisandrin significantly alleviated the Aβ1–42 oligomer-induced loss of mitochondrial membrane potential and impaired cytochrome c oxidase activity. Additionally, the opening of mitochondrial permeability transition pore and release of cytochrome c were highly restricted with schisandrin treatment. Alterations in cell viability, ATP production, citrate synthase activity, and the expressions of glycolysis-related enzymes demonstrated the relief of defective energy metabolism in Aβ-treated neurons after the treatment of schisandrin. For mitochondrial biogenesis, elevated expression of peroxisome proliferator-activated receptor γ coactivator along with promoted mitochondrial mass was found in schisandrin-treated cells. The imbalance in the cycle of fusion and fission was also remarkably restored by schisandrin. In summary, this study provides novel mechanisms for the protective effect of schisandrin on mitochondria-related functions.

scholarly journals Nuclear Gene Dosage Effects Upon the Expression of Maize Mitochondrial Genes

Genetics ◽  
2001 ◽  
Vol 157 (4) ◽  
pp. 1711-1721
Author(s):  
Donald L Auger ◽  
Kathleen J Newton ◽  
James A Birchler
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Gene Dosage ◽  
Nuclear Gene ◽  
Eukaryotic Cell ◽  
Mitochondrial Genes ◽  
Northern Analysis ◽  
Α Subunit ◽  
Dosage Effects ◽  
A Genome

Abstract Each mitochondrion possesses a genome that encodes some of its own components. The nucleus encodes most of the mitochondrial proteins, including the polymerases and factors that regulate the expression of mitochondrial genes. Little is known about the number or location of these nuclear factors. B-A translocations were used to create dosage series for 14 different chromosome arms in maize plants with normal cytoplasm. The presence of one or more regulatory factors on a chromosome arm was indicated when variation of its dosage resulted in the alteration in the amount of a mitochondrial transcript. We used quantitative Northern analysis to assay the transcript levels of three mitochondrially encoded components of the cytochrome c oxidase complex (cox1, cox2, and cox3). Data for a nuclearly encoded component (cox5b) and for two mitochondrial genes that are unrelated to cytochrome c oxidase, ATP synthase α-subunit and 18S rRNA, were also determined. Two tissues, embryo and endosperm, were compared and most effects were found to be tissue specific. Significantly, the array of dosage effects upon mitochondrial genes was similar to what had been previously found for nuclear genes. These results support the concept that although mitochondrial genes are prokaryotic in origin, their regulation has been extensively integrated into the eukaryotic cell.

scholarly journals Mutations in nuclear gene cyt-4 of Neurospora crassa result in pleiotropic defects in processing and splicing of mitochondrial RNAs.

Genetics ◽  
1989 ◽  
Vol 123 (1) ◽  
pp. 97-108 ◽  
Author(s):  
K F Dobinson ◽  
M Henderson ◽  
R L Kelley ◽  
R A Collins ◽  
A M Lambowitz
Keyword(s):  
Neurospora Crassa ◽  
Mitochondrial Protein ◽  
Nuclear Gene ◽  
Northern Hybridization ◽  
Rrna Gene ◽  
Mitochondrial Rna ◽  
Group I Introns ◽  
Group I ◽  
Processing Pathways ◽  
Aberrant Rna

Abstract The nuclear cyt-4 mutants of Neurospora crassa have been shown previously to be defective in splicing the group I intron in the mitochondrial large rRNA gene and in 3' end synthesis of the mitochondrial large rRNA. Here, Northern hybridization experiments show that the cyt-4-1 mutant has alterations in a number of mitochondrial RNA processing pathways, including those for cob, coI, coII and ATPase 6 mRNAs, as well as mitochondrial tRNAs. Defects in these pathways include inhibition of 5' and 3' end processing, accumulation of aberrant RNA species, and inhibition of splicing of both group I introns in the cob gene. The various defects in mitochondrial RNA synthesis in the cyt-4-1 mutant cannot be accounted for by deficiency of mitochondrial protein synthesis or energy metabolism, and they suggest that the cyt-4-1 mutant is defective in a component or components required for processing and/or turnover of a number of different mitochondrial RNAs. Defective splicing of the mitochondrial large rRNA intron in the cyt-4-1 mutant may be a secondary effect of failure to synthesize pre-rRNAs having the correct 3' end. However, a similar explanation cannot be invoked to account for defective splicing of the cob pre-mRNA introns, and the cyt-4-1 mutation may directly affect splicing of these introns.

Curcumin induces mitochondrial biogenesis by increasing cAMP levels via PDE4A inhibition in skeletal muscle

2021 ◽  
pp. 1-34
Author(s):  
Hamidie Ronald D Ray ◽  
Tsubasa Shibaguchi ◽  
Tatsuya Yamada ◽  
Rikuhide Koma ◽  
Rie Ishizawa ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Expression ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Respiration ◽  
Citrate Synthase ◽  
Signalling Pathway ◽  
Curcumin Treatment ◽  
Camp Content ◽  
Signalling Molecules ◽  
Camp Levels

Abstract Background: Previous research has suggested that curcumin potentially induces mitochondrial biogenesis in skeletal muscle via increasing cAMP levels. However, the regulatory mechanisms for this phenomenon remain unknown. The purpose of the present study was to clarify the mechanism by which curcumin activates cAMP-related signalling pathways that upregulate mitochondrial biogenesis and respiration in skeletal muscle. Methods: The effect of curcumin treatment (i.p., 100 mg/kg-BW/day for 28 days) on mitochondrial biogenesis was determined in rats. The effects of curcumin and exercise (swimming for 2 h/day for 3 days) on the cAMP signalling pathway were determined in the absence and presence of phosphodiesterase (PDE) or protein kinase A (PKA) inhibitors. Mitochondrial respiration, citrate synthase (CS) activity, cAMP content, and protein expression of cAMP/PKA signalling molecules were analysed. Results: Curcumin administration increased COX-IV protein expression, and CS and complex I activity, consistent with the induction of mitochondrial biogenesis by curcumin. Mitochondrial respiration was not altered by curcumin treatment. Curcumin and PDE inhibition tended to increase cAMP levels with or without exercise. In addition, exercise increased the phosphorylation of PDE4A, whereas curcumin treatment strongly inhibited PDE4A phosphorylation regardless of exercise. Furthermore, curcumin promoted AMPK phosphorylation and PGC-1α deacetylation. Inhibition of PKA abolished the phosphorylation of AMPK. Conclusion: The present results suggest that curcumin increases cAMP levels via inhibition of PDE4A phosphorylation, which induces mitochondrial biogenesis through a cAMP/PKA/AMPK signalling pathway. Our data also suggest the possibility that curcumin utilizes a regulatory mechanism for mitochondrial biogenesis that is distinct from the exercise-induced mechanism in skeletal muscle.

scholarly journals Rat uterine microbiochemistry: metabolic enzyme activities stimulated by 17-beta-estradiol are localized in epithelial cells.

1987 ◽  
Vol 35 (6) ◽  
pp. 657-662 ◽  
Author(s):  
J P Holt ◽  
E Rhe
Keyword(s):  
Enzyme Activity ◽  
Smooth Muscle ◽  
Epithelial Cells ◽  
Dose Response ◽  
Enzyme Activities ◽  
Time Course ◽  
Citrate Synthase ◽  
Ovariectomized Rats ◽  
Similar Response ◽  
Estradiol Treatment

Lactate dehydrogenase (LDH; EC 1.1.1.27), citrate synthase (CS; EC 4.1.3.7), and beta-hydroxyacyl-CoA-dehydrogenase (beta-OH-acyl-CoA-DH; EC 1.1.1.35) activities were determined in each of the three major cell types of rat uterus, i.e., epithelial, stromal, and smooth muscle, using quantitative microanalytical techniques. Adult ovariectomized rats were treated with 17-beta-estradiol to determine the time course and dose response (0.025-50 micrograms/300-g rat) effect of estrogen on enzyme activity of each type of uterine cell. The use of "oil well" and enzyme-cycling microtechniques to determine the time course and the dose responses of enzyme activity changes required microassays involving 1595 microdissected single cell specimens. Estradiol treatment increased epithelial LDH, CS and beta-OH-acyl-CoA-DH activity but had no effect on these enzymes in the stroma or in smooth muscle cells. The estradiol-stimulated peak enzyme activities on Day 4 in the intervention group are compared with those in the ovariectomized rat controls as follows: LDH, 44.5 +/- 3.5 vs 22.3 +/- 3.9; CS, 3.5 +/- 0.2 vs 1.5 +/- 0.6; beta-OH-acyl-CoA-H, 3.5 +/- 0.32 vs 2.2 +/- 0.2 (mean +/- standard deviation; mol/kg/hr). Stromal cell activities (LDH, 7.4 +/- 1.0; CS, 1.2 +/- 0.2; beta-OH-acyl-CoA-DH, 0.9 +/- 0.1) were significantly lower than epithelial cell levels and were similar to smooth muscle levels. Therefore, even in the ovariectomized animal epithelial cells have markedly higher metabolic activity compared with adjacent cells. The enzyme activities are expressed as moles of substrate reacting per kilogram of dry weight per hour. All three enzymes exhibited a 17-beta-estradiol-induced dose response between 0.025-0.15 micrograms/300-g rat. The three enzymes studied all had similar response patterns to estrogen. The effect of estradiol was restricted to epithelial cells, with enzyme activities increasing to maximal levels after approximately 96 hr of hormone treatment. This study therefore not only confirms the specific and differential metabolic responses of uterine cells to estradiol treatment, but clearly demonstrates that marked metabolic differences exist between epithelial cells and stromal or smooth muscle uterine cells.

Selected Contribution: Effects of contractile activity on mitochondrial transcription factor A expression in skeletal muscle

2001 ◽  
Vol 90 (1) ◽  
pp. 389-396 ◽  
Author(s):  
Joe W. Gordon ◽  
Arne A. Rungi ◽  
Hidetoshi Inagaki ◽  
David A. Hood
Keyword(s):  
Skeletal Muscle ◽  
Transcription Factor ◽  
Mitochondrial Biogenesis ◽  
Contractile Activity ◽  
Regulatory Protein ◽  
Mrna Levels ◽  
Mitochondrial Transcription ◽  
Mitochondrial Transcription Factor ◽  
Mitochondrial Transcription Factor A ◽  
Mitochondrial Transcript

Mitochondrial transcription factor A (Tfam) is a nuclear-encoded gene product that is imported into mitochondria and is required for the transcription of mitochondrial DNA (mtDNA). We hypothesized that conditions known to produce mitochondrial biogenesis in skeletal muscle would be preceded by an increase in Tfam expression. Therefore, rat muscle was stimulated (10 Hz, 3 h/day). Tfam mRNA levels were significantly elevated (by 55%) at 4 days and returned to control levels at 14 days. Tfam import into intermyofibrillar (IMF) mitochondria was increased by 52 and 61% ( P < 0.05) at 5 and 7 days, respectively. This corresponded to an increase in the level of import machinery components. Immunoblotting data indicated that IMF Tfam protein content was increased by 63% ( P < 0.05) at 7 days of stimulation. This was associated with a 49% ( P < 0.05) increase in complex formation at the mtDNA promoter and a 65% ( P< 0.05) increase in the levels of a mitochondrial transcript, cytochrome- c oxidase (COX) subunit III. Similarly, COX enzyme activity was elevated by 71% ( P < 0.05) after 7 days of contractile activity. These results indicate that early events in mitochondrial biogenesis include increases in Tfam mRNA, followed by accelerations in mitochondrial import and increased Tfam content, which correspond with increased binding to the mtDNA promoter region. This was accompanied by increased mitochondrial transcript levels and elevated COX activity. These data support the role of Tfam as a regulatory protein involved in contractile activity-induced mitochondrial biogenesis.

Inter-tissue differences in mitochondrial enzyme activity, RNA and DNA in rainbow trout (Oncorhynchus mykiss)

1998 ◽  
Vol 201 (24) ◽  
pp. 3377-3384 ◽  
Author(s):  
S. C. Leary ◽  
B. J. Battersby ◽  
C. D. Moyes
Keyword(s):  
Enzyme Activity ◽  
Rainbow Trout ◽  
Oncorhynchus Mykiss ◽  
Citrate Synthase ◽  
Mitochondrial Protein ◽  
Molecular Organization ◽  
Mitochondrial Rna ◽  
Mitochondrial Enzyme ◽  
Rainbow Trout Oncorhynchus Mykiss ◽  
The Relationship

We examined whether the relationships between mitochondrial enzyme activity, mitochondrial DNA (mtDNA) and mitochondrial RNA (mtRNA) were conserved in rainbow trout (Oncorhynchus mykiss) tissues that differ widely in their metabolic and molecular organization. The activity of citrate synthase (CS), expressed either per gram of tissue or per milligram of total DNA, indicated that these tissues (blood, brain, kidney, liver,cardiac, red and white muscles) varied more than 100-fold in mitochondrial content. Several-fold differences in the levels of CS mRNA per milligram of DNA and CS activity per CS mRNA were also observed, suggesting that fundamental differences exist in the regulation of CS levels across tissues. Although tissues varied 14-fold in RNA g-1, poly(A+) RNA (mRNA)was approximately 2 % of total RNA in all tissues. DNA g-1 also varied 14-fold across tissues, but RNA:DNA ratios varied only 2.5-fold. The relationship between two mitochondrial mRNA species (COX I, ATPase VI) and one mitochondrial rRNA (16S) species was constant across tissues. The ratio of mtRNA to mtDNA was also preserved across most tissues; red and white muscle had 10- to 20-fold lower levels of mtDNA g-1 but 7- to 10-fold higher mtRNA:mtDNA ratios, respectively. Collectively, these data suggest that the relationship between mitochondrial parameters is highly conserved across most tissues, but that skeletal muscles differ in a number of important aspects of respiratory gene expression ('respiratory genes'include genes located on mtDNA and genes located in the nucleus that encode mitochondrial protein) and mtDNA transcriptional regulation.

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