Impaired energy metabolism in rat myocardium during phosphate depletion

Brautbar, Nachman; Baczyński, R; Carpenter, Carol A.; Moser, Sandra; Geiger, Paul J.; Finander, P.; Massry, Shaul G.

doi:10.1152/ajprenal.1982.242.6.f699

Cited by 19 publications

(27 citation statements)

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“…On the basis of these comparisons, we conclude that easy fatigability and delayed recovery of muscle strength following fatigue are early manifestations of the myopathy produced by phosphate deficiency. The biochemical changes produced in skeletal muscle by phosphate deficiency in this study are consistent with the findings noted in cardiac muscle by others (11,13) and support the hypothesis of a defect in energy metabolism of the myocyte in this condition. Prior studies (11,13) suggest that energy metabolism of the myocyte may be disrupted at several different stages in phosphate deficiency.…”

Section: Discussionsupporting

confidence: 92%

“…The biochemical changes produced in skeletal muscle by phosphate deficiency in this study are consistent with the findings noted in cardiac muscle by others (11,13) and support the hypothesis of a defect in energy metabolism of the myocyte in this condition. Prior studies (11,13) suggest that energy metabolism of the myocyte may be disrupted at several different stages in phosphate deficiency. Mitochondrial high energy phosphate (ATP) synthesis via oxidative phosphorylation may be defective; transformation of energy generated in the mitochondria into CP for transport to the myofibril may be abnormal; and resynthesis of ATP from CP at the myofibril to supply the energy needed for muscle contraction may be impaired.…”

Section: Discussionsupporting

confidence: 92%

“…Models that produce the greatest reductions in serum phosphorous concentration are associated with a more severe myopathy, which is characterized by muscle wasting, weakness with even modest activity, and diminished ATP levels in resting cardiac and skeletal muscle (10,11,13,16,17,22). Even in these severely phosphate-deficient animals, the myopathy is reversible following phosphate supplementation (10,16).…”

Section: Discussionmentioning

confidence: 99%

“…These studies suggest that INTRODUCTION Hypophosphatemia and intracellular deficiency of inorganic phosphate result in dysfunction of a wide range of organ systems in man and experimental animals. Erythrocyte hemolysis (1-3), derangements in the mechanical and phagocytic properties of leukocytes (1, 4), decreased survival and abnormal function of platelets (1,5), central nervous system abnormalities compatible with metabolic encephalopathy (1,6,7), abnormalities in renal function (1,8), and cardiac (1,(9)(10)(11)13), and skeletal myopathy (1,(12)(13)(14)(15)(16)(17) have been described in patients or animals with phosphate deficiency.…”

mentioning

confidence: 99%

“…The mechanisms proposed include shifts in the hemoglobin-02 dissociation curve leading to tissue hypoxia (6,18,19), inhibition of glycolysis and glycogenolysis (3,6,20), impaired calcium metabolism (8,10,17), alterations in phospholipid content of cellular membranes (17), diminished intracellular ATP stores secondary to a defect in ATP synthesis (1, 8, 11-13, 16-18, 21, 22), and disruption of energy transport from the mitochondria to the myofibril via the creatine phosphate (CP)' shuttle (11,13). The latter two mechanisms, i.e., a defect in ATP synthesis and a defect in energy utilization, may be of particular relevance in explaining the muscle dysfunction observed in phosphate deficiency, since both energy production in the form of ATP synthesis in the mitochondria and energy use in the form of CP transfer to ADP at the myofibril increase manyfold during vigorous muscle contraction (23,24).…”

mentioning

confidence: 99%

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Defective adenosine triphosphate synthesis. An explanation for skeletal muscle dysfunction in phosphate-deficient mice.

Hettleman¹,

Sabina²,

Drezner³

et al. 1983

J. Clin. Invest.

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A B S T R A C T The basis for skeletal muscle dysfunction in phosphate-deficient patients and animals is not known, but it is hypothesized that intracellular phosphate deficiency leads to a defect in ATP synthesis. To test this hypothesis, changes in muscle function and nucleotide metabolism were studied in an animal model of hypophosphatemia. Mice were made hypophosphatemic through restriction of dietary phosphate intake. Gastrocnemius function was assessed in situ by recording isometric tension developed after stimulation of the nerve innervating this muscle. Changes in purine nucleotide, nucleoside, and base content of the muscle were quantitated at several time points during stimulation and recovery.Serum concentration and skeletal muscle content of phosphorous are reduced by 55 and 45%, respectively, in the dietary restricted animals. The gastrocnemius muscle of the phosphate-deficient mice fatigues more rapidly compared with control mice. ATP and creatine phosphate content fall to a comparable extent during fatigue in the muscle from both groups of animals; AMP, inosine, and hypoxanthine (indices of ATP catabolism) appear in higher concentration in the muscle of phosphate-deficient animals. Since total ATP use in contracting muscle is closely linked to total developed tension, we conclude that the comparable drop in ATP content in association with a more rapid loss of tension is best explained by a slower rate of ATP synthesis in the muscle of phosphate-deficient animals. During the period of recovery after muscle stimulation, ATP use for contraction is minimal, since the muscle is at rest. In the recovery period, ATP content returns to resting levels more slowly in the phosphate-deficient than in the control animals. In association with the slower rate of ATP repletion, the precursors inosine monophosphate and AMP remain elevated for a longer period of time in the muscle of phosphate-deficient animals. The slower rate of ATP repletion correlates with delayed return of normal muscle contractility in the phosphate-deficient mice. These studies suggest that the slower rate of repletion of the ATP pool may be the consequence of a slower rate of ATP synthesis and this is in part responsible for the delayed recovery of normal muscle contractility.

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