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

Abstract

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.

Effect of Parathyroid Hormone on Rat Skeletal Muscle in vivo

“…In comparably severe hypophosphataemia of non-parathyroid origin, there may be severe abnormal ities in mitochondrial metabolism studied in vitro [11] and in vivo [10,27]. It has usually been assumed that this is related to a critical decrease in cell [Pi] [11,27], although little such decrease is seen by 31P MRS [10,12], The present study makes this argument less plausible by showing that cell [Pi] may be reduced acutely by 40% without any detectable bioenergetic abnormalities.…”

Adenosine triphosphate turnover in humans. Decreased degradation during relative hyperphosphatemia.

“…In hypophosphatemic mice skeletal muscle weakness and renal cortical changes have been associated with elevated levels of AMP, inosine, and hypoxanthine (5,6,27 (1-4, 15). This results from a diminution in intracellular phosphate levels secondary to the accumulation offructose-1-phosphate and the reduced synthesis ofATP from ADP in mitochondria (1-4, 29).…”

“…Consequently, a phosphate-deprived state may be associated with decreased ATP synthesis and increased formation ofATP degradation products. Indeed, hypophosphatemia increases ATP degradation products in skeletal muscle (5,6) and is correlated with a myriad of clinical manifestations in-cluding hemolytic anemia, respiratory failure, myopathy, and neurologic abnormalities in humans (7)(8)(9)(10)(11)(12)(13)(14).…”

Disruption of the purine nucleotide cycle by inhibition of adenylosuccinate lyase produces skeletal muscle dysfunction.

“…The total volume infused during the course of the experiment averaged 0.86±0.03 ml. The left gastrocnemius muscle was carefully dissected free of surrounding tissues with its nerve and blood supply intact (22). The soleus, plantaris, and rectus femoris muscles were dissected free of the gastrocnemius muscle and removed from the preparation.…”

“…The leg was secured with a steel pin through the femur and a screw clamp over the hind paw, and the limb was immersed in a 370C mineral oil bath. The distal tendon of the gastrocnemius muscle was attached to a Grass FT.03 force transducer with a stainless steel rod (22). Muscle length was then adjusted to provide maximal isometric tension.…”