Role of UCP3 in state 4 respiration during contractile activity-induced mitochondrial biogenesis

Ljubicic, Vladimir; Adhihetty, Peter J.; Hood, David A.

doi:10.1152/japplphysiol.00336.2004

Cited by 38 publications

(48 citation statements)

References 63 publications

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“…TA muscles were quickly excised and immediately placed in ice-cold buffer, briefly minced, and homogenized. Differential centrifugation was used to fractionate SS and IMF mitochondria, as described previously (11,30,45). Mitochondria were resuspended in medium (100 mM KCl, 10 mM MOPS, and 0.2% BSA) and subsequently used for mitochondrial respiration, ROS production, and mtPTP opening.…”

Section: Methodsmentioning

confidence: 99%

“…Isolated SS and IMF mitochondria were incubated with V O2 buffer [250 mM sucrose, 50 mM KCl, 25 mM Tris ⅐ HCl, 10 mM K 2HPO4, and 0.2% BSA (pH 7.4)] with continuous stirring at 30°C in a water-encased respiratory compartment. V O2 (natoms O2 ⅐ min Ϫ1 ⅐ mg Ϫ1 ) was assessed in the presence of 11 mM glutamate (state 4 respiration) or 0.4 mM ADP (state 3 respiration) with a Clark oxygen electrode (Yellow Springs Instruments, Yellow Springs, OH), as described previously (2,11,30).…”

Section: Methodsmentioning

confidence: 99%

“…Frozen rat muscles were pulverized to a fine powder in a stainless steel mortar cooled with liquid nitrogen. Powdered tissues were diluted 1:20 (wt/vol) in 100 mM Na-K-phosphate extraction buffer (pH 7.2) containing 2 mM EDTA in the absence of protease or phosphatase inhibitors and processed as previously described (30). Whole muscle protein extracts were separated by 12% SDS-PAGE and subsequently transferred to nitrocellulose membranes.…”

Section: Methodsmentioning

confidence: 99%

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Effect of denervation on mitochondrially mediated apoptosis in skeletal muscle

Adhihetty¹,

O'Leary²,

Chabi³

et al. 2007

Journal of Applied Physiology

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211

240

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November 22, 2006; doi:10.1152/japplphysiol.00768.2006.-Chronic muscle disuse induced by denervation reduces mitochondrial content and produces muscle atrophy. To investigate the molecular mechanisms responsible for these adaptations, we assessed 1) mitochondrial biogenesis-and apoptosis-related proteins and 2) apoptotic susceptibility and cell death following denervation. Rats were subjected to 5, 7, 14, 21, or 42 days of unilateral denervation of the sciatic or peroneal nerve. Muscle mass and mitochondrial content were reduced by 40 -65% after 21 and 42 days of denervation. Denervation-induced decrements in mitochondrial content occurred along with 60% and 70% reductions in transcription factor A (Tfam) and peroxisome proliferator-activated receptor-␥ coactivator (PGC)-1␣, respectively. After 42 days of denervation, Bax was elevated by 115% and Bcl-2 was decreased by 89%, producing a 16-fold increase in the Bax-toBcl-2 ratio. Mitochondrial reactive oxygen species production was markedly elevated by 5-to 7.5-fold in subsarcolemmal mitochondria after 7, 14, and 21 days of denervation, whereas reactive oxygen species production in intermyofibrillar (IMF) mitochondria was reduced by 40 -50%. Subsarcolemmal and IMF mitochondrial levels of MnSOD were also reduced by 40 -50% after 14 -21 days of denervation. The maximal rate of IMF mitochondrial pore opening (Vmax) was elevated by 25-35%, and time to V max was reduced by 20 -25% after 14 and 21 days, indicating increased apoptotic susceptibility. Myonuclear decay, assessed by DNA fragmentation, was elevated at 7-21 days of denervation. Our data indicate that PGC-1␣ and Tfam are important factors that likely contribute to the reduced mitochondrial content after chronic disuse. In addition, our results illustrate that, despite the reduced mitochondrial content, denervated muscle has greater mitochondrial apoptotic susceptibility, which coincided with elevated apoptosis, and these processes may contribute to denervation-induced muscle atrophy. mitochondrial biogenesis; muscle disuse; reactive oxygen species; mitochondrial respiration; peroxisome proliferator-activated receptor-␥ coactivator-1␣

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Effect of denervation on mitochondrially mediated apoptosis in skeletal muscle

Adhihetty¹,

O'Leary²,

Chabi³

et al. 2007

Journal of Applied Physiology

Self Cite

211

240

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“…The TA muscles were extracted, weighed, blotted to remove excess liquid, quickly minced, and homogenized. Differential centrifugation was used to separate the SS and the IMF mitochondrial subfractions as previously described (19). Isolated SS and IMF mitochondrial subfractions were resuspended in medium (100 mM KCl, 10 mM MOPS, 0.2% BSA) and used for the analysis of mitochondrial respiration, reactive oxygen species (ROS) production, and protein composition.…”

Section: Methodsmentioning

confidence: 99%

Effect of prior chronic contractile activity on mitochondrial function and apoptotic protein expression in denervated muscle

O'Leary

Hood²

2008

Journal of Applied Physiology

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O'Leary MF, Hood DA. Effect of prior chronic contractile activity on mitochondrial function and apoptotic protein expression in denervated muscle. J Appl Physiol 105: 114 -120, 2008. First published May 1, 2008 doi:10.1152/japplphysiol.00724.2007.-Skeletal muscle is highly adaptable in response to increases and decreases in contractile activity. The purpose of this study was to determine whether the preconditioning of skeletal muscle has a protective effect against subsequent denervation-induced apoptotic protein expression. To investigate this, we chronically stimulated the tibialis anterior and extensor digitorum longus muscles for 7 days (10 Hz, 3 h/day) before 7 days of denervation. Denervation reduced total cytochrome-c oxidase activity by 39%, which was likely a consequence of a decrease in subsarcolemmal (SS) mitochondria. This decrease in the SS subfraction was prevented by prior chronic stimulation and, as a result, maintained total mitochondrial content at control levels. The expression of Bax was elevated 2.2-fold by denervation, and prior chronic stimulation did not attenuate this increase. This produced a increase in the Bax-to-Bcl-2 ratio, indicating greater muscle apoptotic susceptibility. Denervation also decreased state 3 respiration in SS and intermyofibrillar mitochondria and elevated state 4 reactive oxygen species production within both mitochondrial subfractions. These changes were not prevented by prior chronic stimulation. Furthermore, the antioxidant protein MnSOD was also reduced by denervation, whereas Beclin-1 was markedly elevated. This suggests that autophagic cell death could also play a significant part in denervationinduced muscle atrophy. Thus, despite prior chronic stimulation, denervation increases the apoptotic susceptibility of skeletal muscle by altering the Bax-to-Bcl-2 ratio, by increasing reactive oxygen species production, and by reducing the expression of MnSOD. Whether a more extensive stimulation paradigm would be more effective in attenuating apoptosis before muscle disuse remains to be determined. mitochondrial biogenesis; muscle atrophy; reactive oxygen species; autophagy; protein degradation SKELETAL MUSCLE IS AN ADAPTABLE tissue that exhibits a remarkable range of plasticity in response to different levels of contractile activity (15). In particular, chronic contractile activity is known to alter the expression of a variety of proteins from the nuclear and mitochondrial genomes (15). These changes in protein expression result in an increase in mitochondrial volume and density (6, 16). In skeletal muscle, two distinct subfractions of mitochondria exist that are characterized by their anatomic localization. Subsarcolemmal (SS) mitochondria are located just beneath the sarcolemmal membrane, whereas intermyofibrillar (IMF) mitochondria are intertwined between skeletal muscle myofibrils (8). SS and IMF mitochondrial subfractions are significantly increased in response to chronic contractile activity. However, SS mitochondria are more sensitive to endurance training a...

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“…Muscle portions were placed into chilled buffer 1, finely minced, and then homogenized. Differential centrifugation and mechanical and protease digestions were employed to fractionate subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria, as described previously (54). SS and IMF subfractions were resuspended in resuspension medium, and an aliquot of the suspension was taken for measurements of protein content (13).…”

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confidence: 99%

Kinase-specific responsiveness to incremental contractile activity in skeletal muscle with low and high mitochondrial content

Ljubicic

Hood²

2008

American Journal of Physiology-Endocrinology and Metabolism

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Ljubicic V, Hood DA. Kinase-specific responsiveness to incremental contractile activity in skeletal muscle with low and high mitochondrial content. Am J Physiol Endocrinol Metab 295: E195-E204, 2008. First published May 20, 2008 doi:10.1152/ajpendo.90276.2008.-Muscle contractions activate protein kinases, leading to signal transduction. We hypothesized that kinase activation would be influenced by mitochondrial content, as well as by contractile activity-induced increases in muscle O 2 consumption (V O2). Kinase phosphorylation in high-oxidative red and low-oxidative white tibialis anterior (TA) muscle (RTA and WTA, respectively) with 2.5-fold differences in mitochondrial content were compared. Stimulation of the TA muscle elicited large increases in V O2 (3-to 6-fold and 4-to 60-fold above resting levels in WTA and RTA, respectively). At rest, AMP-activated protein kinase (AMPK), p38, p42, and p44 activation were nearly twofold greater in WTA than in RTA, suggesting an inverse relationship between mitochondrial content and kinase activation in resting muscle. During contractions, similar degrees of phosphorylation in RTA and WTA were evident as a function of V O2 for p38 and p42. During increases in V O2 up to sixfold above rest, greater responses were observed in RTA than in WTA for AMPK and p44, whereas Akt activation was greater in WTA. In RTA, elevations in V O2 elicited increases in AMPK and p44 activation, whereas Akt, p38, and p42 were less sensitive to increments in V O2. Reactive oxygen species (ROS) production was greater in mitochondria from white muscle, but when it was calculated in the context of the whole muscle, ROS production was twofold greater in red than in white myofibers. Thus mitochondrial content influences ROS production and is inversely related to kinase activation in resting muscle. During contractions, kinases are differentially sensitive to contraction-induced increments in V O2, suggesting that muscle mitochondrial content is important, but it is not the sole determinant of kinase activation during exercise of different intensities. muscle oxygen consumption; kinase activation; muscle plasticity; signal transduction; mitochondrial biogenesis WITHIN SECONDS OF THE ONSET of contractile activity in skeletal muscle, a number of rapid events occur that form part of the initial signaling process leading to downstream protein and lipid synthesis. These changes include Ca 2ϩ flux, ATP turnover, and stimulation of O 2 consumption (V O 2 ) within the contracting muscle cells. Accumulating evidence supports the link between chronic alterations in these conditions and distinctive programs of gene expression that establish phenotypic diversity among skeletal myofibers, such as hypertrophy or mitochondrial biogenesis. For example, raising cytosolic Ca 2ϩ

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Role of UCP3 in state 4 respiration during contractile activity-induced mitochondrial biogenesis

Cited by 38 publications

References 63 publications

Effect of denervation on mitochondrially mediated apoptosis in skeletal muscle

Effect of denervation on mitochondrially mediated apoptosis in skeletal muscle

Effect of prior chronic contractile activity on mitochondrial function and apoptotic protein expression in denervated muscle

Kinase-specific responsiveness to incremental contractile activity in skeletal muscle with low and high mitochondrial content

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