Skeletal muscle bioenergetics in myotonic dystrophy

Taylor, Doris J.; Kemp, Graham J.; Woods, C. G.; Edwards, J. H.; Radda, George K.

doi:10.1016/0022-510x(93)90325-s

Cited by 32 publications

(28 citation statements)

References 20 publications

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“…Reduced intracellular pH levels have been found in a variety of different diseases, such as heart failure (44), cardiac ischemia/reperfusion (21), chronic administration of sodium/ hydrogen exchanger selective inhibitors in myocardial hypertrophy (11,20,43), and chronic acidosis. Meanwhile, abnormally increased pH levels have been detected in certain muscular dystrophies (e.g., Duchenne, Becker, and myotonic) (45,50,75). These disease-related pH changes would be anticipated to affect MLP/CFL2 interaction and actin depolymerization, with direct implications for myocyte cytoarchitecture and function (Fig.…”

Section: Discussionmentioning

confidence: 99%

Muscle Lim Protein Interacts with Cofilin 2 and Regulates F-Actin Dynamics in Cardiac and Skeletal Muscle

Papalouka

Arvanitis

Vafiadaki

et al. 2009

Molecular and Cellular Biology

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The muscle LIM protein (MLP) and cofilin 2 (CFL2) are important regulators of striated myocyte function. Mutations in the corresponding genes have been directly associated with severe human cardiac and skeletal myopathies, and aberrant expression patterns have often been observed in affected muscles. Herein, we have investigated whether MLP and CFL2 are involved in common molecular mechanisms, which would promote our understanding of disease pathogenesis. We have shown for the first time, using a range of biochemical and immunohistochemical methods, that MLP binds directly to CFL2 in human cardiac and skeletal muscles. The interaction involves the inter-LIM domain, amino acids 94 to 105, of MLP and the amino-terminal domain, amino acids 1 to 105, of CFL2, which includes part of the actin depolymerization domain. The MLP/CFL2 complex is stronger in moderately acidic (pH 6.8) environments and upon CFL2 phosphorylation, while it is independent of Ca 2؉ levels. This interaction has direct implications in actin cytoskeleton dynamics in regulating CFL2-dependent F-actin depolymerization, with maximal depolymerization enhancement at an MLP/ CFL2 molecular ratio of 2:1. Deregulation of this interaction by intracellular pH variations, CFL2 phosphorylation, MLP or CFL2 gene mutations, or expression changes, as observed in a range of cardiac and skeletal myopathies, could impair F-actin depolymerization, leading to sarcomere dysfunction and disease.The muscle LIM protein (MLP) has emerged as a critical player in striated muscle physiology and pathophysiology over recent years. MLP, encoded by the CSRP3 (or CRP3) gene, is a member of the conserved LIM-only protein family since it contains two LIM functional zinc finger domains, and it is expressed exclusively in muscle cells. Specifically, in differentiating striated muscle cells, MLP localizes in the nucleus, promoting myogenic differentiation (8), while in adult muscle, it translocates to the cytoplasm and assumes an essential role in myocyte cytoarchitecture. Through its interactions with structural proteins, such as alpha-actinin, telethonin (T-cap), ␤I-spectrin, and N-RAP, MLP has been suggested to act as a scaffold protein for the basic contractile unit, the sarcomere, and the actin-based cytoskeleton (7,9,25,27,46,73).Mutations in CSRP3 have been directly associated with dilated (DCM) and hypertrophic (HCM) cardiomyopathies (9,31,32,46). HCM is the most common genetic myocardial disease, with a prevalence of 0.2% in adults, and the most frequent cause of sudden cardiac death in young individuals, while DCM is the third most common cause of heart failure (54,55,76). Genetic aberrations in MLP have been shown to lead to marked actin cytoskeleton disorganization and disrupted cardiac myofibrillar cytoarchitecture (9). Similar observations have been described for skeletal muscles, and HCM-CSRP3 mutations have been associated with mild skeletal myopathy (9, 31). Various hypotheses, including an MLP role in mechanical stretch sensing or the mechanical stress response, have...

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Section: Discussionmentioning

confidence: 99%

Muscle Lim Protein Interacts with Cofilin 2 and Regulates F-Actin Dynamics in Cardiac and Skeletal Muscle

Papalouka

Arvanitis

Vafiadaki

et al. 2009

Molecular and Cellular Biology

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“…In all reports of patients suffering from GSD II, muscle protein wasting is supposed to occur, but detailed information on alterations in lean body mass or muscle protein content is lacking. In a number of cases, muscular dystrophies have been associated with a decreased oxidative capacity,9, 21, 23, 24, 32, 38 but for GSD II this information is not available. Despite glycogen storage in nervous tissue, electromyographic (EMG) findings in patients with GSD II are reportedly normal 3, 12.…”

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confidence: 99%

Impaired performance of skeletal muscle in α‐glucosidase knockout mice

et al. 2002

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Glycogen storage disease type II (GSD II) is an inherited progressive muscle disease in which lack of functional acid alpha-glucosidase (AGLU) results in lysosomal accumulation of glycogen. We report on the impact of a null mutation of the acid alpha-glucosidase gene (AGLU(-/-)) in mice on the force production capabilities, contractile mass, oxidative capacity, energy status, morphology, and desmin content of skeletal muscle. Muscle function was assessed in halothane-anesthetized animals, using a recently designed murine isometric dynamometer. Maximal torque production during single tetanic contraction was 50% lower in the knockout mice than in wild type. Loss of developed torque was found to be disproportionate to the 20% loss in muscle mass. During a series of supramaximal contraction, fatigue, expressed as percentile decline of developed torque, did not differ between AGLU(-/-) mice and age-matched controls. Muscle oxidative capacity, energy status, and protein content (normalized to either dry or wet weight) were not changed in knockout mice compared to control. Alterations in muscle cell morphology were clearly visible. Desmin content was increased, whereas alpha-actinin was not. As the decline in muscle mass is insufficient to explain the degree in decline of mechanical performance, we hypothesize that the large clusters of noncontractile material present in the cytoplasm hamper longitudinal force transmission, and hence muscle contractile function. The increase in muscular desmin content is most likely reflecting adaptations to altered intracellular force transmission.

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“…However, similar to what is seen after a complete spinal cord transection in rats (Durozard, Gabrielle et al 2000), the trend towards an increase in the resting [Pi]/[PCr] ratios after a cSCI is accompanied with concurrent decreases in the [PCr] content. The exact mechanism of declines in [PCr] content at rest remains unknown, but is suggestive of an imbalance in the resting phosphorylation potential such that the energy available for muscle contraction and other cellular work is decreased (Taylor, Kemp et al 1993). Additionally, similar to spinal transection in rats (Durozard, Gabrielle et al 2000), we observed a slight increase in the baseline pH values; possibly indicating a shift to anaerobic metabolism after paralysis.…”

Section: Discussionmentioning

confidence: 99%

“…When measuring oxidative capacity using MRS, it is essential to prevent muscle acidosis. This is because pH declines below 6.75 units (Taylor, Kemp et al 1993; McCully, Iotti et al 1994; Boesch 2007) significantly impacts k PCr rates and cannot adequately reflect skeletal muscle oxidative capacity. In the present study, the end stimulation pH was 6.9 and did not decrease by more than 0.2 units as compared to the baseline pH in either the SCI or control groups.…”

Section: Discussionmentioning

confidence: 99%

“…Consequently, the paralyzed muscle will function less economically than normal and require more energy to perform a given contraction. Moreover, increases in ATP consumption of paralyzed muscle can also result from ATP consuming events in the tissue such as muscle atrophy (Erkintalo, Bendahan et al 1998) and the uncoupling of oxidative phosphorylation (Taylor, Kemp et al 1993; Scheuermann-Freestone, Madsen et al 2003). However, confirmation from actual measurements of the energy cost of contractions, by the amount of ATP produced for a given power output in the rat model of moderate cSCI are warranted.…”

Section: Discussionmentioning

confidence: 99%

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In vivo 31P NMR spectroscopy assessment of skeletal muscle bioenergetics after spinal cord contusion in rats

Shah

Liu

et al. 2014

Eur J Appl Physiol

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Purpose Muscle paralysis after spinal cord injury (SCI) leads to muscle atrophy, enhanced muscle fatigue, and increased energy demands for functional activities. Phosphorus magnetic resonance spectroscopy (31P-MRS) offers a unique non-invasive alternative of measuring energy metabolism in skeletal muscle and is especially suitable for longitudinal investigations. We determined the impact of spinal cord contusion on in-vivo muscle bioenergetics of the rat hindlimb muscle using 31P-MRS. Methods A moderate spinal cord contusion injury (cSCI) was induced at the T8-T10 thoracic spinal segments. 31P-MRS measurements were performed weekly in the rat hindlimb muscles for three weeks. Spectra were acquired in a Bruker 11T/470 MHz spectrometer using a 31P surface coil. The sciatic nerve was electrically stimulated by subcutaneous needle electrodes. Spectra were acquired at rest (5 min), during stimulation (6 min), and recovery (20 min). Phosphocreatine (PCr) depletion rates and the pseudo-first-order rate constant for PCr recovery (kPCr) were determined. The maximal rate of PCr resynthesis, the in-vivo maximum oxidative capacity (Vmax) and oxidative ATP synthesis rate (Qmax), were subsequently calculated. Results One week after cSCI, there was a decline in the resting [TCr] of the paralyzed muscle. There was a significant reduction (~24%) in kPCr measures of the paralyzed muscle, maximum in-vivo mitochondrial capacity (Vmax) and the maximum oxidative ATP synthesis rate (Qmax) at 1week post-cSCI. Conclusions Using in-vivo MRS assessments, we reveal an acute oxidative metabolic defect in the paralyzed hind limb muscle. These altered muscle bioenergetics might contribute to the host of motor dysfunctions seen after cSCI.

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Skeletal muscle bioenergetics in myotonic dystrophy

Cited by 32 publications

References 20 publications

Muscle Lim Protein Interacts with Cofilin 2 and Regulates F-Actin Dynamics in Cardiac and Skeletal Muscle

Muscle Lim Protein Interacts with Cofilin 2 and Regulates F-Actin Dynamics in Cardiac and Skeletal Muscle

Impaired performance of skeletal muscle in α‐glucosidase knockout mice

In vivo 31P NMR spectroscopy assessment of skeletal muscle bioenergetics after spinal cord contusion in rats

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