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

Saini-Chohan, Harjot K.; Mitchell, Ryan W.; Vaz, Frédéric M.; Zelinski, Teresa; Hatch, Grant M.

doi:10.1194/jlr.r012120

Cited by 47 publications

(40 citation statements)

References 298 publications

(344 reference statements)

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“…Cardiac involvement is the leading cause of early death in patients wtih DMD (63), and intramyocardial lipid accumulation in cardiac muscle has been observed in patients wtih DMD, especially in the most damaged areas of the hearts (11, 13). We hypothesized that IMCL observed in the mdx and dKO mice was not limited to the skeletal muscle but would also be found in cardiac muscle and could be related to the formation of fibrosis observed in the dystrophic hearts (cardiomyopathy) of the mice.…”

Section: Resultsmentioning

confidence: 99%

“…Duchenne muscular dystrophy (DMD) features progressive muscle degeneration and has no cure yet. Obesity occurs in >50% of patients wtih DMD after 14 yr of age, and a reduction in myocardial fatty acid metabolism has been observed in ~50% of patients wtih DMD (10, 11). FI is commonly observed in the skeletal muscles of patients wtih DMD, and it is one of the main factors responsible for patients' decline in muscular strength (12).…”

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confidence: 99%

“…FI is commonly observed in the skeletal muscles of patients wtih DMD, and it is one of the main factors responsible for patients' decline in muscular strength (12). Lipid mapping analysis of the hearts and skeletal muscles of patients wtih DMD revealed IMCL within the most damaged areas of the dystrophic muscles (11, 13); however, there are very few studies on the mechanisms and prevention of IMCL in patients wtih DMD. Although less documented in human patients wtih DMD, the presence of HO has been reported in the skeletal muscles of various animal models of human DMD, including mdx mice and golden retriever muscular dystrophy (GRMD) dogs (14–16).…”

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confidence: 99%

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RhoA mediates defective stem cell function and heterotopic ossification in dystrophic muscle of mice

Ūsas

Tang

et al. 2013

FASEB j.

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Heterotopic ossification (HO) and fatty infiltration (FI) often occur in diseased skeletal muscle and have been previously described in various animal models of Duchenne muscular dystrophy (DMD); however, the pathological mechanisms remain largely unknown. Dystrophin-deficient mdx mice and dystrophin/utrophin double-knockout (dKO) mice are mouse models of DMD; however, mdx mice display a strong muscle regeneration capacity, while dKO mice exhibit a much more severe phenotype, which is similar to patients with DMD. Our results revealed that more extensive HO, but not FI, occurred in the skeletal muscle of dKO mice versus mdx mice, and RhoA activation specifically occurred at the sites of HO. Moreover, the gene expression of RhoA, BMPs, and several inflammatory factors were significantly up-regulated in muscle stem cells isolated from dKO mice; while inactivation of RhoA in the cells with RhoA/ROCK inhibitor Y-27632 led to reduced osteogenic potential and improved myogenic potential. Finally, inactivation of RhoA signaling in the dKO mice with Y-27632 improved muscle regeneration and reduced the expression of BMPs, inflammation, HO, and intramyocellular lipid accumulation in both skeletal and cardiac muscle. Our results revealed that RhoA represents a major molecular switch in the regulation of HO and muscle regeneration in dystrophic skeletal muscle of mice.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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RhoA mediates defective stem cell function and heterotopic ossification in dystrophic muscle of mice

Ūsas

Tang

et al. 2013

FASEB j.

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“…Fats can go directly to the heart and skeletal muscle, where they can accumulate and impair organ/tissue function (cardiomyopathy/myopathy). Free fatty acids and long-chain acylcarnitines can alter the electrical activity of cardiac cells resulting in arrhythmia [3, 78–80]. In certain diseases, the muscle fibers can also break down during sustained exercise resulting in myoglobinuria [3, 81].…”

Section: Disorders Of Fatty Acid Oxidationmentioning

confidence: 99%

Carnitine transport and fatty acid oxidation

Longo

Frigeni

Pasquali

2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

594

469

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Carnitine is essential for the transfer of long-chain fatty acids across the inner mitochondrial membrane for subsequent β-oxidation. It can be synthesized by the body or assumed with the diet from meat and dairy products. Defects in carnitine biosynthesis do not routinely result in low plasma carnitine levels. Carnitine is accumulated by the cells and retained by kidneys using OCTN2, a high affinity organic cation transporter specific for carnitine. Defects in the OCTN2 carnitine transporter results in autosomal recessive primary carnitine deficiency characterized by decreased intracellular carnitine accumulation, increased losses of carnitine in the urine, and low serum carnitine levels. Patients can present early in life with hypoketotic hypoglycemia and hepatic encephalopathy, or later in life with skeletal and cardiac myopathy or sudden death from cardiac arrhythmia, usually triggered by fasting or catabolic state. This disease responds to oral carnitine that, in pharmacological doses, enters cells using the amino acid transporter B0,+. Primary carnitine deficiency can be suspected from the clinical presentation or identified by low levels of free carnitine (C0) in the newborn screening. Some adult patients have been diagnosed following the birth of an unaffected child with very low carnitine levels in the newborn screening. The diagnosis is confirmed by measuring low carnitine uptake in the patients’ fibroblasts or by DNA sequencing of the SLC22A5 gene encoding the OCTN2 carnitine transporter. Some mutations are specific for certain ethnic backgrounds, but the majority are private and identified only in individual families. Although the genotype usually does not correlate with metabolic or cardiac involvement in primary carnitine deficiency, patients presenting as adults tend to have at least one missense mutation retaining residual activity.

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“…CPT1 and CPT2, genes critical for very long-chain fatty acid production and membrane stabilization, were down-regulated. Congenital deficiencies in these genes are associated with hypertrophic cardiomyopathy, diastolic dysfunction, and arrhythmias (17).…”

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confidence: 99%

The heart in sickle cell disease, a model for heart failure with preserved ejection fraction

Wood

2016

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

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

Cited by 47 publications

References 298 publications

RhoA mediates defective stem cell function and heterotopic ossification in dystrophic muscle of mice

RhoA mediates defective stem cell function and heterotopic ossification in dystrophic muscle of mice

Carnitine transport and fatty acid oxidation

The heart in sickle cell disease, a model for heart failure with preserved ejection fraction

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