Mechanism of Muscle Wasting in Myotonic Dystrophy Robert C. Griggs, MD,” Ralph Jozefowicz, MD,” William Kingston, MD,” K. Sreekumaran Nair, MD, PhD,” Barbara E. Herr, MS,” and David Halliday, PhDt Myotonic dystrophy is associated with progressive muscular atrophy. In order to determine the mechanism of muscle wasting in this condition, we measured fractional mixed skeletal muscle protein synthesis in the postabsorptive state in 8 patients with myotonic dystrophy, and compared the results with those of 10 normal subjects. Fractional muscle protein synthesis was determined by measuring the increment of 13Cleucine in mixed skeletal muscle protein obtained by needle biopsy from the quadriceps muscle during a primed-continuous infusion of G(l-13C)leucine. We used plasma 13C a-ketoisocaproate (representing intracellular leucine labeling) as the precursor pool for the calculation of fractional muscle protein synthesis and leucine kinetics. Fractional muscle protein synthesis was depressed in the patients with myotonic dystrophy (28% decrease, p < 0.02). Leucine flux, leucine oxidation, and the nonoxidative portion of leucine flux were not different between the patients with myotonic dystrophy and the normal control subjects. Muscle atrophy in myotonic dystrophy reflects a selective decrease in muscle protein synthesis without any similar decrease in nonmuscle protein synthesis. This decrease may result from an impaired end-organ response to anabolic hormones or substrates. Griggs RC, Jozefowicz R, Kingston W, Nair KS, Herr BE, Halliday D. Mechanism of muscle wasting in myotonic dystrophy. Ann Neurol 1990;27:505-5 12 Myotonic dystrophy is a multisystemic autosomal dominant disorder transmitted by a locus on the long arm of chromosome 19 111. Many of the clinical manifestations of myotonic dystrophy can be treated but the progressive muscle wasting and weakness are as yet of unknown cause and not amenable to treatment {2f. Myotonic dystrophy differs from other muscular dystrophies in that muscle wasting histologically represents atrophy rather than necrosis of muscle {3}. In contrast to the changes found in disorders characterized by “active myopathy,” concentrations of creatine kinase and other muscle enzymes are often normal in the serum of patients with myotonic dystrophy {2). The atrophic rather than “dystrophic” character of the disorder has led to the suggestion that myotonic dystrophy is the consequence of either denervation {4} or a membrane abnormality { S } , resulting in a reduction of a cellular response to anabolic hormone(s){G]. Patients with myotonic dystrophy, in contrast to Duchenne dystrophy or denervating illnesses such as amyotrophic lateral sclerosis, have a marked absolute decrease in the excretion of 3-methylhistidine, which remains low when corrected for muscle mass determined by creatinine excretion {7}. This finding sug-

gests that a defect in protein synthesis rather than an increase in proteolysis is the cause of muscle atrophy 181. The use of stable isotopes permits the direct study of whole body and skeletal muscle protein synthesis 19- 121. Previous attempts to measure muscle protein synthesis in patients with muscular dystrophies were done while the patients were fed at regular intervals during the study period { l l , 131. Such studies do not distinguish clearly between endogenous leucine flux and exogenous flux since leucine in the meal is not labeled. There is also uncertainty about the precursor pool labeling when amino acids appear endogenously from proteolysis, and exogenously from food. It is possible that the precursor pool labeling for protein synthesis is affected more by the gradient of amino acids across the cell membrane than the intracellular amino acids { 141. The assumption that intracellular labeling and plasma labeling are the same as labeling of amino acyl transfer RNA (tRNA) could, therefore, be erroneous during a meal. Such theoretical problems relative to precursor pool labeling for calculating protein synthesis are less when studies are done in the postabsorptive state [lo]. In the postabsorptive state the de

From the *Department of Neurology, University of Rochester, School of Medicine, Rochester, NY, and ?The Nutrition Research Grow, C ~ N Research d Centre, Harrow, Middlesex, United E W dom. Received May 26, 1989, and in revised form Sep 1. Accepted for

“Present Address: Endocrinology/Metabolism Unit, College of Medicine, University of Vermont, Burlington, VT 05405. Address correspondence to D~~ ~ D~~~~~~ j ~of ~ ~ , ~ Box 673, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642.

publication Nov 3,1989.

Copyright 0 1990 by the American Neurological Association

505

~

Table I . Subject Data

Subjects Patients 1 . l

L

3 4 5 6 7 8 Mean 2 SEM Normal subjects Mean SEM p Value

*

Age (yr)

Weight (kg)

Height (m)

Muscle Mass (from 24-hr Creatinine Excretion) (kg)

33

62 71 74 66 58 64 75 62 66 f 2

1.70 1.75 1.74 1.61 1.51 1.80 1.74 1.75 1.70 ? 0.03

21 21 15 26 21 29 26 28 23 2 2

62 86 72 72 85 78 84 80 77 2 3

NA 13 NA 14 18 10 14 14 14 & 1

1.78 2 0.02

36

85 2 2 c0.05

7-11 0.2

73

2