Increased lysosomal enzymes in genetic muscular dystrophy

Tappel, Al L.; Zalkin, Howard; Caldwell, Kenneth A.; Desai, I. D.; Shibko, S.

doi:10.1016/0003-9861(62)90418-6

Cited by 161 publications

(36 citation statements)

References 24 publications

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“…In addition, several lysosomal enzymes appear to increase in muscles of dystrophic animals (27,28) (although invasion by foreign cells may contribute to these effects).…”

Section: Discussionmentioning

confidence: 99%

Thyroid hormones control lysosomal enzyme activities in liver and skeletal muscle

DeMartino

Goldberg

1978

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

132

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Because protein degradation in liver and skeletal muscle is increased by thyroid hormones and decreased by thyroidectomy, we investigated the influence of thyroid hormones on the level of lysosomal enzymes. Hypophysectomized rats received daily injections of L-thyroxine or L-triiodothyronine. After 3 days of this regimen, homogenates of liver and skeletal muscle showed a 2-to 3-fold increase in the activities of cathepsin D, cathepsin B, and other lysosomal enzymes including leucine aminopeptidase, acid phosphatase, i3-galactosidase, N-acetylglucosaminidase, and a-mannosidase.In liver, this effect reflected increased enzyme activity in the two subcellular fractions that normally contain lysosomes. Titration of cathepsin D with pepstatin indicated that the increase in this activity resulted from an increase in the number of enzyme molecules. These effects occurred with both pharmacologic (thyrotoxic) and physiologic (growth-promoting) doses of thyroid hormones. Liver and skeletal muscle from thyroidectomized rats had approximately 50% of the normal levels of lysosomal enzyme activities. Under these various conditions, heart and kidney, tissues in which protein degradation does not appear to be influenced by thyroid hormones, showed no significant changes in lysosomal hydrolases. Thus, thyroid hormones regulate proteolytic and other lysosomal enzyme activities in those tissues in which these hormones influence protein degradation. Many characteristic features of hyperthyroidism and hypothyroidism may result from changes in levels of lysosomal enzymes.In mammalian cells, several hormones are known to regulate the average rates of protein degradation (1, 2). For example, in liver, insulin decreases overall proteolysis (3, 4) whereas glucagon stimulates this process (5, 6), and these effects are important in regulating protein content of this organ (2). Recent studies (7,8) in this laboratory demonstrated that thyroid hormones also have important effects on average rates of protein degradation in addition to other known effects in promoting protein synthesis. Thyroidectomy or hypophysectomy, either of which greatly diminishes thyroid hormone production, decreased protein degradation in skeletal muscles of rats. Physiologic doses of thyroxine (T4) or triiodothyronine (T3) induced muscle growth and increased both protein synthesis and protein degradation. Higher doses of these hormones increased protein degradation further but did not change protein synthesis rates beyond those observed with growth-promoting doses. Thus, the severe muscle wasting observed in hyperthyroidism appears to result from increased protein degradation. In addition, thyroid hormones were found to increase protein degradation in liver but not in heart or kidney (7). The present studies were undertaken to clarify the mechanism by which thyroid hormones influence protein catabolism.Mammalian tissues contain both lysosomal and nonlysosomal proteases (2). Although certain proteins (e.g., proteins with abnormal conformations) appear to be degr...

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“…In addition, several lysosomal enzymes appear to increase in muscles of dystrophic animals (27,28) (although invasion by foreign cells may contribute to these effects).…”

Section: Discussionmentioning

confidence: 99%

Thyroid hormones control lysosomal enzyme activities in liver and skeletal muscle

DeMartino

Goldberg

1978

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

132

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“…However, in both these forms of muscle wasting, the specific activities (activity per gram weight of muscle or activity per milligram of protein nitrogen) of a number of acid hydrolases (hydrolytic enzymes with maximum activity in the acid pH range) are increased [20,24,28,33,35,38,40]. In nutritional muscular dystrophy the total activity (activity in an entire muscle or muscle group) of cathepsin is also increased [24], The high elevation in specific activities of other acid hydrolases in dystrophic muscle indi cates that total activities of these hydrolases may be similarly elevated.…”

Section: And M Lukacsmentioning

confidence: 99%

Enzyme Studies in Muscular Dystrophy V

Weinstock

Lukacs

1965

Enzymol Biol Clin

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The separate and concurrent effects of nutritional muscular dystrophy, induced by vitamin E-deficiency, and of denervation atrophy on wet weight, noncollagen protein nitrogen and deoxyribonucleic acid content, and on the activities of six acid hydrolases in the hamstring muscles of rabbits have been investigated. There are similarities in the patterns of increased acid hydrolase activity in both conditions, although in nutritional dystrophy the increments are much greater. Loss of muscle mass and noncollagen protein nitrogen content are much greater in denervation atrophy than in nutritional muscular dystrophy, whereas only in the latter condition is there a marked increase in deoxyribonucleic acid content. The effects of both conditions occurring simultaneously appear to be additive. The results also suggest that the increased activities of hydrolytic enzymes represent a common enzymatic mechanism that is involved in the loss of muscle mass and that most of the increments in hydrolase activity of dystrophic muscle originate from the pathological muscle cells themselves and may partially reflect attempts at regeneration.

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“…An increased acid cathepsin activity has been found in muscular dystrophies of both nutritional [4,8,17,19] and genetic origin [4,16,18], and in denervation atrophy in various species [3,5]. Human muscle was found to have cathepsin activity against myoglobin substrate over a wide pH range, with peaks at 3.9 and 6.6.…”

Section: Introductionmentioning

confidence: 99%

Acid, Neutral and Alkaline Cathepsins in Normal and Diseased Human Muscle

Nc¹,

Cm²

1972

Enzyme

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Homogenates of human skeletal muscle showed autolytic and cathepsin activity over a wide pH range with peaks at 3.6, 6.6 and 8.6. Some evidence was presented for the enzymatic and proteolytic nature of the autolytic process. Both myoglobin and hemoglobin were equally active as substrates at all pH peaks. In mildly abnormal muscle of patients with Duchenne muscular dystrophy, other dystrophies, dermatomyositis and neurogenic atrophies, both autolytic and cathepsin activity in the acid, neutral and alkaline range were either normal or slightly above normal. On the other hand, in severely degenerated muscles of patients with the same disease conditions, large increases in autolytic and cathepsin activity at all pH peaks were found. The increased activity of cathepsins was found to correlate with the degree of muscle degeneration. These results suggest that the cathepsins are involved in the muscle wasting process in human muscle diseases.

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Increased lysosomal enzymes in genetic muscular dystrophy

Cited by 161 publications

References 24 publications

Thyroid hormones control lysosomal enzyme activities in liver and skeletal muscle

Thyroid hormones control lysosomal enzyme activities in liver and skeletal muscle

Enzyme Studies in Muscular Dystrophy V

Acid, Neutral and Alkaline Cathepsins in Normal and Diseased Human Muscle

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