Dystrophin-dependent efficiency of metabolic pathways in mouse skeletal muscles

Abstract

Muscles from the mdx mouse (X-linked genetic disorder similar to Duchenne muscular dystrophy) lack dystrophin-associated transsarcolemmal proteins and show reduced maintenance metabolic rates. Here, microcalorimetric comparisons of metabolic stimulation by exogenous substrates in isolated muscles revealed substrate-selective limitation of chemical reaction rates through both glycolytic and TCA-cycle pathways, identical in slow- and fast-twitch mdx muscles. This systemic approach, as opposed to comparisons of single-enzyme activities, sheds new light on the function of dystrophin and associated proteins. The in vivo efficiency of metabolic pathways may depend on stabilization of enzyme complexes by dystrophin-associated elements of the cytoskeleton.

Quantitative Proteomic Analysis Reveals Metabolic Alterations, Calcium Dysregulation, and Increased Expression of Extracellular Matrix Proteins in Laminin α2 Chain–deficient Muscle

“…Similar metabolic crises and mitochondrial abnormalities have been reported in gene and/or proteome expression profiling of different types of muscular dystrophy, including Duchenne muscular dystrophy and sarcoglycanopathy (56,57), and biochemical studies unveiled limitations in glycolytic and tricarboxylic acid cycle pathways and defective regulation of energy metabolism in mdx mice (58,59). Also, metabolic defects in ␤-sarcoglycan-deficient mice have been reported (60).…”

Effect of intraperitoneal injection of glucose on glucose oxidation and energy expenditure in the mdx mouse model of Duchenne muscular dystrophy

“…Other studies have revealed a high glycogen concentration in mdx mouse muscle [6] suggesting that a decreased proportion of glucose uptake was oxidised in muscles from mdx mice [20]. On the other hand, we have observed that utilisation of glucose, pyruvate, acetylene dicarboxylate and free fatty acids, but not fumarate, was decreased in mdx mouse muscle [4,12]. This observation agreed with observations by Glesby et al [15] on isolated mitochondria that oxidation of nicotinamide adenine dinucleotide(NAD)-but not flavin adenine dinucleotide(FAD)-linked substrates could be impaired in the mdx mouse muscle.…”

“…This observation agreed with observations by Glesby et al [15] on isolated mitochondria that oxidation of nicotinamide adenine dinucleotide(NAD)-but not flavin adenine dinucleotide(FAD)-linked substrates could be impaired in the mdx mouse muscle. In contrast, addition of pantothenate (vitamin B s) to stimulate production of coenzyme A (CoA) increased glucose-derived heat production more in mdx than in control mouse muscles [4,12]. In line with these in vitro studies, in vivo studies on the free moving mdx mouse have shown that the feedinginduced increase in whole body glucose oxidation (G 0 ) was less in mdx mice [21] which suggested a possible alteration of skeletal muscle energy metabolism in situ since skeletal muscles contribute a significant part of post prandial G0 [9,17].…”

Impaired metabolic modulation of α-adrenergic vasoconstriction in dystrophin-deficient skeletal muscle

“…For example, the metabolic response to muscle contraction may be altered in mdx mice because of a transition in regenerating muscle from fast-twitch glycolytic fibers to slow-twitch oxidative fibers (31)(32)(33). In addition, the lack of dystrophin and consequent disruption of the cytoskeletal organization may negatively impact the cytosolic and mitochondrial enzymes involved in energy production (34,35). Although we cannot completely discount these alternative explanations, the conclusion that metabolic modulation of ␣-adrenergic vasoconstriction in contracting skeletal muscle is tightly coupled to the production of NO is supported by the observation that the mdx phenotype was mimicked both by pharmacological NOS inhibition in the C57 mice and by nNOS gene deletion in the nNOS knockout mice.…”