Effects of ischemia on skeletal muscle energy metabolism in mice lacking creatine kinase monitored byin vivo31P nuclear magnetic resonance spectroscopy

Zandt, René in ‘t; Oerlemans, Frank; Wieringa, B.; Heerschap, Arend

doi:10.1002/(sici)1099-1492(199910)12:6<327::aid-nbm570>3.0.co;2-9

Cited by 33 publications

(30 citation statements)

References 36 publications

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“…We used conventional mRNA profiling on cDNA arrays to obtain insight into mechanisms that play a role in sensing of – and the response to – metabolic stress in the CK‐mediated high‐energy phosphoryl shuttle. Earlier our group had already uncovered important functional and structural differences between M‐CK −/− , CK −/− and wild‐type muscles [10,11,15], most of which were associated with rather subtle changes in the level of a diverse series of mitochondrial, cytoarchitectural and glycolytic proteins [12]. Based on these findings we have postulated that most – if not all – of these changes may in fact have a compensatory character, serving to ameliorate the adverse physiological effects of gene ablation [10,11].…”

Section: Discussionmentioning

confidence: 83%

Changes in mRNA expression profile underlie phenotypic adaptations in creatine kinase‐deficient muscles

et al. 2001

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We have studied the mechanisms that regulate the remodeling of the glycolytic, mitochondrial and structural network of muscles of creatine kinase M (M-CK)/sarcomeric mitochondrial creatine kinase (ScCKmit) knockout mice by comparison of wild-type and mutant mRNA profiles on cDNA arrays. The magnitudes of changes in mRNA levels were most prominent in M-CK/ScCKmit (CK 3a3 ) double mutants but did never exceed those of previously observed changes in protein level for any protein examined. In gastrocnemius of CK 3a3 mice we measured a 2.5-fold increase in mRNA level for mitochondrial encoded cytochrome c oxidase (COX)-III which corresponds to the increase in protein content. The level of the nuclear encoded mRNAs for COX-IV, H + -ATP synthase-C, adenine nucleotide translocator-1 and insulin-regulatable glucose transporter-4 showed a 1.5-fold increase, also in agreement with protein data. In contrast, no concomitant up-regulation in mRNA and protein content was detected for the mitochondrial inorganic phosphatecarrier, voltage-dependent anion channel and certain glycolytic enzymes. Our results reveal that regulation of transcript level plays an important role, but it is not the only principle involved in the remodeling of mitochondrial and cytosolic design of CK 3a3 muscles. ß

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Section: Discussionmentioning

confidence: 83%

Changes in mRNA expression profile underlie phenotypic adaptations in creatine kinase‐deficient muscles

et al. 2001

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“…While, strikingly, ATP levels are decreased and P i is increased in Cr‐depleted AGAT −/− muscle, ATP levels in CK =/= muscle were comparable to normal WT muscle, and only mild elevations in P i /β‐ATP ratios were observed in basal conditions (Steeghs et al 1997 a , b ). However, in CK =/= mice the P i /ATP ratios can be increased by an ischaemic period, without recovery for at least a day thereafter (in 't Zandt et al 1999). Moreover, both CK =/= and AGAT −/− muscle demonstrate abnormal functionality; depleted AGAT −/− mice suffer from a reduced grip strength, while the absence of the PCr–CK system results in a lack of burst activity upon electric stimulation (de Haan et al 1995; Steeghs et al 1998).…”

Section: Discussionmentioning

confidence: 99%

“…The 1 H MR measurements of skeletal muscle of the lower hindlimb were performed using a solenoid radio frequency coil positioned at the magic angle with respect to the B 0 field (in 't Zandt et al 1999). Multislice gradient echo images (repetition time (TR) = 250 ms, echo time (TE) = 5 ms, field of view (FOV) 20 mm × 20 mm, 256 × 256 matrix) were used to guide the positioning of 16 μl voxels in the tibialis anterior/extensor digitorus longus region.…”

Section: Methodsmentioning

confidence: 99%

“…To assess the role and capacity of the the PCr–CK system in skeletal muscle, we monitored by 31 P MRS the dynamic changes in ATP, PCr, P i and pH upon ischaemic occlusion of the hindlimb in AGAT −/− and WT mice. Reversible obstruction of blood flow through hindlimb skeletal muscle was accomplished in the MR magnet by clamping the hindlimb above the knee with a diaphragm plate (in 't Zandt et al 1999). The 31 P spectra were acquired with a time resolution of 1.46 min (TR = 1400 ms, 76 averages) for 7 min prior to the ischaemic period, and during 25 min of ischaemia and 16 min of recovery (Kan et al 2004).…”

Section: Methodsmentioning

confidence: 99%

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Disturbed energy metabolism and muscular dystrophy caused by pure creatine deficiency are reversible by creatine intake

Nabuurs

Choe

Veltien

et al. 2013

The Journal of Physiology

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Key points• Creatine (Cr) plays an important role in muscle energy homeostasis as a substrate in the creatine kinase phosphoryl exchange reaction, but the consequences of creatine depletion are incompletely understood.• We assessed the morphological, metabolic and functional consequences of systemic creatine depletion on skeletal muscle in a mouse model with deficiency of an essential enzyme in the biosynthesis of creatine (AGAT −/− mice).• We show that Cr depletion leads to several metabolic abnormalities in muscle, including reduced ATP, increased inorganic phosphate levels and reduced activities of proton-pumping respiratory chain enzymes and an elevated glycolytic contribution in ischaemic circumstances.• The Cr-depleted muscle suffers from reduced grip strength, severe atrophy and abnormal mitochondrial structures, increased overall mitochondrial content and an increased number of lipid droplets.• Oral Cr administration led to rapid accumulation in skeletal muscle (faster than in brain) and reversed all the muscle abnormalities, revealing that the condition of the AGAT −/− mice can be switched between Cr deficient and normal simply by dietary manipulation.Abstract Creatine (Cr) plays an important role in muscle energy homeostasis by its participation in the ATP-phosphocreatine phosphoryl exchange reaction mediated by creatine kinase. Given that the consequences of Cr depletion are incompletely understood, we assessed the morphological, metabolic and functional consequences of systemic depletion on skeletal muscle in a mouse model with deficiency of L-arginine:glycine amidinotransferase (AGAT −/− ), which catalyses the first step of Cr biosynthesis. In vivo magnetic resonance spectroscopy showed a near-complete absence of Cr and phosphocreatine in resting hindlimb muscle of AGAT −/− mice. Compared with wild-type, the inorganic phosphate/β-ATP ratio was increased fourfold, while ATP levels were reduced by nearly half. Activities of proton-pumping respiratory chain C. I. Nabuurs and C. U. Choe contributed equally to this work. enzymes were reduced, whereas F 1 F 0 -ATPase activity and overall mitochondrial content were increased. The Cr-deficient AGAT −/− mice had a reduced grip strength and suffered from severe muscle atrophy. Electron microscopy revealed increased amounts of intramyocellular lipid droplets and crystal formation within mitochondria of AGAT −/− muscle fibres. Ischaemia resulted in exacerbation of the decrease of pH and increased glycolytic ATP synthesis. Oral Cr administration led to rapid accumulation in skeletal muscle (faster than in brain) and reversed all the muscle abnormalities, revealing that the condition of the AGAT −/− mice can be switched between Cr deficient and normal simply by dietary manipulation. Systemic creatine depletion results in mitochondrial dysfunction and intracellular energy deficiency, as well as structural and physiological abnormalities. The consequences of AGAT deficiency are more pronounced than those of muscle-specific creatine kinase deficiency, which suggests...

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“…31 P-MRS studies have shown a reduction of energy metabolism in the ischemic muscle [33]–[37]. Since unphosphorylated creatine (Cr) is inaccessible with 31 P-MRS, 1 H-MRS can be a reliable tool for expressing the Cr and PCr contributions as a percent of tCr.…”

Section: Discussionmentioning

confidence: 99%

MR Angiography, MR Imaging and Proton MR Spectroscopy In-Vivo Assessment of Skeletal Muscle Ischemia in Diabetic Rats

et al. 2012

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To prospectively evaluate the feasibility of using magnetic resonance (MR) techniques for in-vivo assessing a rat diabetic model of limb ischemia. Unilateral hind limb ischemia was induced by ligation of the iliac-femoral artery in male streptozotocin-treated and non-diabetic control rats. Four weeks after ligation, rats underwent MR Angiography (MRA), T1-weighted and Short Time Inversion Recovery (STIR) sequences and muscle Proton MR Spectroscopy (1H-MRS) on both hind limbs. After MR examinations, immunoblotting and immunofluorescence analysis were performed. MRA showed a signal void due to flow discontinuation distal to the artery ligation. T1-weighted and STIR images showed, respectively, the presence of tissue swelling (p = 0.018 for non-diabetic; p = 0.027 for diabetic rats) and signal hyperintensity in tissue affected by occlusion. Mean total creatine/water for the occluded limb was significantly lower than for the non-occluded limbs in both non-diabetic (5.46×10−4 vs 1.14×10−3, p = 0.028) and diabetic rats (1.37×10−4 vs 1.10×10−3; p = 0.018). MR Imaging and 1H-MRS changes were more pronounced in diabetic than in non-diabetic occluded limbs (p = 0.032). MR findings were confirmed by using histological findings. Combined MR techniques can be used to demonstrate the presence of structural and metabolic changes produced by iliac-femoral artery occlusion in rat diabetic model of limb ischemia.

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Effects of ischemia on skeletal muscle energy metabolism in mice lacking creatine kinase monitored byin vivo31P nuclear magnetic resonance spectroscopy

Cited by 33 publications

References 36 publications

Changes in mRNA expression profile underlie phenotypic adaptations in creatine kinase‐deficient muscles

Changes in mRNA expression profile underlie phenotypic adaptations in creatine kinase‐deficient muscles

Disturbed energy metabolism and muscular dystrophy caused by pure creatine deficiency are reversible by creatine intake

MR Angiography, MR Imaging and Proton MR Spectroscopy In-Vivo Assessment of Skeletal Muscle Ischemia in Diabetic Rats

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