Skeletal muscle metabolism in Duchenne muscular dystrophy (DMD): an in-vitro proton NMR spectroscopy study

Sharma, Uma; Atri, Surinder Kumar; Sharma, Mehar Chand; Sarkar, Chitra; Jagannathan, Naranamangalam R.

doi:10.1016/s0730-725x(02)00646-x

Cited by 88 publications

(88 citation statements)

References 55 publications

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“…Disruption of the amount or distribution of phospholipids results in major defects in cellular membranes (45). Decreases in PC have been found in muscle membranes of the dy mouse (a model of congenital muscular dystrophy) and in human Duchenne muscular dystrophy (46,47) and LGMD (48) patients, as compared with normal individuals, underscoring the role of phospholipids in maintaining membrane stability of muscle tissues. A potential role for abnormal membrane lipid composition has been reported in sickle cell anemia (49) and Refsum disease (50).…”

Section: Discussionmentioning

confidence: 99%

A Rostrocaudal Muscular Dystrophy Caused by a Defect in Choline Kinase Beta, the First Enzyme in Phosphatidylcholine Biosynthesis

Sher

Aoyama

Huebsch

et al. 2006

Journal of Biological Chemistry

110

102

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Muscular dystrophies include a diverse group of genetically heterogeneous disorders that together affect 1 in 2000 births worldwide. The diseases are characterized by progressive muscle weakness and wasting that lead to severe disability and often premature death. Rostrocaudal muscular dystrophy (rmd) is a new recessive mouse mutation that causes a rapidly progressive muscular dystrophy and a neonatal forelimb bone deformity. The rmd mutation is a 1.6-kb intragenic deletion within the choline kinase beta (Chkb) gene, resulting in a complete loss of CHKB protein and enzymatic activity. CHKB is one of two mammalian choline kinase (CHK) enzymes (␣ and ␤) that catalyze the phosphorylation of choline to phosphocholine in the biosynthesis of the major membrane phospholipid phosphatidylcholine. While mutant rmd mice show a dramatic decrease of CHK activity in all tissues, the dystrophy is only evident in skeletal muscle tissues in an unusual rostral-to-caudal gradient. Minor membrane disruption similar to dysferlinopathies suggest that membrane fusion defects may underlie this dystrophy, because severe membrane disruptions are not evident as determined by creatine kinase levels, Evans Blue infiltration, and unaltered levels of proteins in the dystrophin-glycoprotein complex. The rmd mutant mouse offers the first demonstration of a defect in a phospholipid biosynthetic enzyme causing muscular dystrophy, representing a unique model for understanding mechanisms of muscle degeneration.Muscular dystrophies are a variable class of more than 20 human disorders characterized by progressive muscle wasting and weakness resulting from myofiber degeneration and regeneration. Histologically, variation in myofiber size with centrally localized nuclei, fibrosis, and fatty infiltration are common features (1, 2). Despite their common pathologies, the genetic causes, severity, age of onset, and inheritance patterns vary widely among the dystrophies. The Muscular Dystrophy Association currently lists over 40 neuromuscular diseases as targets for its research programs and categorizes them by phenotypic characteristics such as age of onset, affected muscle groups, and inheritance pattern (Muscular Dystrophy Association, www.mdausa.org). In the last 10 years, the genetic mapping and identification of novel skeletal muscle genes, including cytoskeletal, cytosolic, nuclear membrane, sarcolemmal and extracellular matrix proteins, has dramatically changed this phenotype-based classification and provided clues as to the molecular basis of these disorders (3). What was once considered a single disease entity such as limb-girdle muscular dystrophy (LGMD) 4 has now been subdivided into seven different molecularly defined autosomal dominant (LGMD1A-1G) and ten autosomal recessive (LGMD2A-2J) diseases. Not surprisingly, many of these genes have converged to define pathways critical for the normal functioning and maintenance of skeletal muscles. The fact that many muscular dystrophy cases exist in which mutations to known dystrophy-causing genes have...

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Section: Discussionmentioning

confidence: 99%

A Rostrocaudal Muscular Dystrophy Caused by a Defect in Choline Kinase Beta, the First Enzyme in Phosphatidylcholine Biosynthesis

Sher

Aoyama

Huebsch

et al. 2006

Journal of Biological Chemistry

110

102

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“…In contrast, several studies in DMD patients and animal models have documented abnormalities in muscle substrate and energy metabolism (36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47), prompting the term "metabolic crisis" as a hallmark feature of this disease (41). Given the important role for KLF15 in muscle metabolism, we hypothesized that DMD might be characterized by a state of relative KLF15 deficiency and that GCs may mediate important therapeutic effects in DMD, in part, via induction of KLF15.…”

Section: Klf15 Ismentioning

confidence: 99%

Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program

Morrison‐Nozik

Anand

Zhu

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Classic physiology studies dating to the 1930s demonstrate that moderate or transient glucocorticoid (GC) exposure improves muscle performance. The ergogenic properties of GCs are further evidenced by their surreptitious use as doping agents by endurance athletes and poorly understood efficacy in Duchenne muscular dystrophy (DMD), a genetic muscle-wasting disease. A defined molecular basis underlying these performance-enhancing properties of GCs in skeletal muscle remains obscure. Here, we demonstrate that ergogenic effects of GCs are mediated by direct induction of the metabolic transcription factor KLF15, defining a downstream pathway distinct from that resulting in GC-related muscle atrophy. Furthermore, we establish that KLF15 deficiency exacerbates dystrophic severity and muscle GC-KLF15 signaling mediates salutary therapeutic effects in the mdx mouse model of DMD. Thus, although glucocorticoid receptor (GR)-mediated transactivation is often associated with muscle atrophy and other adverse effects of pharmacologic GC administration, our data define a distinct GR-induced gene regulatory pathway that contributes to therapeutic effects of GCs in DMD through proergogenic metabolic programming.skeletal muscle metabolism | glucocorticoid | exercise | Duchenne muscular dystrophy | steroid hormone nuclear receptor

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“…Carnitine levels in muscle biopsies from patients with DMD, BMD, limb-girdle dystrophy, and polymyositis/dermatomyositis are low/ reduced compared with histologically normal muscle (114)(115)(116). The low values of carnitine seen in these dystrophic patients may be a nonspecifi c effect, possibly related to the severe muscle damage.…”

mentioning

confidence: 98%

“…The low values of carnitine seen in these dystrophic patients may be a nonspecifi c effect, possibly related to the severe muscle damage. Proton NMR analysis in biopsied skeletal muscle from DMD patients demonstrated, in addition to reduced levels of choline-containing lipids indicative of membrane abnormalities, a decrease in acetate-containing lipids that is indicative of reduced transport of fatty acids into mitochondria due to decreased carnitine concentrations (115 ). Indeed, in approximately 50% of DMD patients examined, a reduction in myocardial fatty acid metabolism was indicated by reduced uptake and metabolism of a radioiodinated branched fatty acid ( 118 ).…”

mentioning

confidence: 99%

Delineating the role of alterations in lipid metabolism to the pathogenesis of inherited skeletal and cardiac muscle disorders

Saini-Chohan

Mitchell

Vaz

et al. 2012

Journal of Lipid Research

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Skeletal muscle metabolism in Duchenne muscular dystrophy (DMD): an in-vitro proton NMR spectroscopy study

Cited by 88 publications

References 55 publications

A Rostrocaudal Muscular Dystrophy Caused by a Defect in Choline Kinase Beta, the First Enzyme in Phosphatidylcholine Biosynthesis

A Rostrocaudal Muscular Dystrophy Caused by a Defect in Choline Kinase Beta, the First Enzyme in Phosphatidylcholine Biosynthesis

Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program

Delineating the role of alterations in lipid metabolism to the pathogenesis of inherited skeletal and cardiac muscle disorders

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