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The sarcoplasmic reticulum in thyrotoxic hypoxalemic periodic paralysis
Metabolism Clinical and Experimental VOL.
XVIII,
NO. 2
FEBRUARY,
1969
The Sarcoplasmic Reticulum in Thyrotoxic Hypoxalemic Periodic Paralysis ByH. S.
SCHUTTAAND J. L. ARMITAGE
Muscle fibers from a case of thyrotoxic hypokalemic periodic paralysis showed distensions of the terminal sacs of the sr with granular material. It is suggested that this may represent excessive calcium
accumulation in the SR, and that studies of calcium metabolism may throw further light on the mechanisms responsible for periodic paralysis. (Metabolism 18: No. 2, February, 81-83, 1969)
HE MECHANISMS which lead to impairment of muscle function in hypokalemic periodic paralysis (h.p.p.) are poorly understood. McArdle,’ reviewing familial h.p.p., pointed out that lowering of serum potassium is only one of many metabolic abnormalities in this disorder. There is evidence to suggest that the defect of carbohydrate metabolism exists in familial h.p.p.,Q but this alone does not explain many of the features of the attacks.l In the course of a fine structure study of a muscle biopsy obtained from a patient with thyrotoxic hypokalemic periodic paralysis at the height of an attack, we have found many myofibers showing abnormalities in the terminal sacs of the sarcoplasmic reticulum (SR). The terminal sacs of the SR, which form contacts with the transverse tubular system, are filled with a finely granular, moderately osmiophilic material, and normally are about 0.1 to 0.2 microns wide. In our biopsy many myofibers were found in which the terminal sacs of the SR were enlarged. It was very common to find the terminal sacs to be 0.4 to 0.6 microns in diameter, but large structures measuring .5 to .8 microns in diameter and 1.2 to 3 microns long were not
T
From the Department of Neurology, University of Pennsylvania School of Medicine and the Pennsylvania Hospital, Philadelphia, Pa. Supported by a grant from the John A. Hartford Foundation, Inc., New York, N.Y., and by Pennsylvania Hospital General Research Support Grant 5SOl FR-05590-02. Received for publication July 29, 1968. HENRY S. SCHUTTA,M.D.: Assistant Professor of Neurology, University of Pennsylvania School of Medicine; Associate Neurologist, Pennsylvania Hospital, Philadelphia, Pa. JAMES L. ARMITAGE, M.D.: Assistant Professor of Neurology, University of Cincinnati; Chief, Neurology Service, Veterans Administration Hospital, Cincinnati, Ohio. 81
SCHUTTA
AND
ARMITAGE
Fig. l.-T-system is clearly visible in several areas (t). Terminal sacs of sarcoplasmic reticulum marked SR 3 and 4 are normal; SR 2, 6 and 7 are slightly enlarged; SR 1 and 5 are moderately enlarged in comparison to SR 3 and 4 X 60,000). Fig 2.-Large ovoid structures marked SR displace t tubule from its normal position at AI injunction. Membrane bounding structures is indistinct; contents is grammlar and appears similar to that in normal and slightly enlarged SR shown in Fig. 1 (X 50,000). uncommon. The T tubules were frequently displaced from their normal position at the A-I junction. Normal appearing triads were intermingled with the abnormal ones ( Figs. 1 and 2). Several investigations have shown that the sarcoplasmic reticulum accumulates calcium ions, and it appears that these are concentrated in the
SARCOPLASMIC
83
RETICULUM
terminal sacs of the SR.3-6 Since the material distending the terminal sacs of the sarcoplasmic reticulum is morphologically quite similar to that found in normal terminal sacs of SR, it is possible that these enlargements may be due to calcium accumulations. Exchange of calcium between the SR and the surrounding myofibrilles evidently plays an important part in the contraction and relaxation processes of muscle. 7,8 Our suggestion that excessive amounts of calcium may accumulate in the SR in thyrotoxic h.p.p. require confirmation. Further studies will show whether this is a universal finding in thyrototic h.p.p. and whether it also applies to familial h.p.p. An excessive accumulation of calcium ions would indicate a disturbance of calcium movements between the SR and the myofibrills, which would most certainly lead to the impairment of muscle function, i.e., paralysis. We believe that studies of muscle calcium metabolism might prove interesting in hypokalemic and possibly other types of periodic paralysis. REFERENCES 1. McArdle, B.: Familial periodic paralysis. Brit. Med. Bull. 12:226, 1956. 2. Shy, G. M., Wanko, T., Rowley, P. T., and Engel, A. G.: Studies in familial periodic paralysis. Exp. Neurol. 3:53, 1961. 3. Constantin, L. L., Franzini-Armstrong, C., and Podolsky, R. J.: Localization of calcium-accumulating structures in striated muscle. Science 147: 158, 1965. 4. Ebashi, S., and Lipman, F.: Adenosine triphosphate-linked concentration of calcium in a particulate fraction of rabbit muscle. J. Cell Biol. 14:389, 1962. 5. Hasselbach, W.: Relaxation and the
sarcotubular calcium pump. Fed. Proc. 23: 909,1964. 6. Martonosi, A., and Feretos, R.: Sarcoplasmic reticulum. I. The uptake of Ca++ by sarcoplasmic reticulum fragments. J. Biol. Chem. 239: 748,1964. 7. Frank, G.: Calcium and other divalent ions in the contraction of skeletal muscle. In Paul, W., Daniel, E. E., and Monckton, G. (Eds.): Muscle. New York, Pergamon Press, 1964, p. 155. 8. Heilburn, L. V., and Wiercinski, F. J.: Action of various cations on muscle protoplasm. J. Cell. Comp. Physiol. 29:15, 1947.
XVIII,
NO. 2
FEBRUARY,
1969
The Sarcoplasmic Reticulum in Thyrotoxic Hypoxalemic Periodic Paralysis ByH. S.
SCHUTTAAND J. L. ARMITAGE
Muscle fibers from a case of thyrotoxic hypokalemic periodic paralysis showed distensions of the terminal sacs of the sr with granular material. It is suggested that this may represent excessive calcium
accumulation in the SR, and that studies of calcium metabolism may throw further light on the mechanisms responsible for periodic paralysis. (Metabolism 18: No. 2, February, 81-83, 1969)
HE MECHANISMS which lead to impairment of muscle function in hypokalemic periodic paralysis (h.p.p.) are poorly understood. McArdle,’ reviewing familial h.p.p., pointed out that lowering of serum potassium is only one of many metabolic abnormalities in this disorder. There is evidence to suggest that the defect of carbohydrate metabolism exists in familial h.p.p.,Q but this alone does not explain many of the features of the attacks.l In the course of a fine structure study of a muscle biopsy obtained from a patient with thyrotoxic hypokalemic periodic paralysis at the height of an attack, we have found many myofibers showing abnormalities in the terminal sacs of the sarcoplasmic reticulum (SR). The terminal sacs of the SR, which form contacts with the transverse tubular system, are filled with a finely granular, moderately osmiophilic material, and normally are about 0.1 to 0.2 microns wide. In our biopsy many myofibers were found in which the terminal sacs of the SR were enlarged. It was very common to find the terminal sacs to be 0.4 to 0.6 microns in diameter, but large structures measuring .5 to .8 microns in diameter and 1.2 to 3 microns long were not
T
From the Department of Neurology, University of Pennsylvania School of Medicine and the Pennsylvania Hospital, Philadelphia, Pa. Supported by a grant from the John A. Hartford Foundation, Inc., New York, N.Y., and by Pennsylvania Hospital General Research Support Grant 5SOl FR-05590-02. Received for publication July 29, 1968. HENRY S. SCHUTTA,M.D.: Assistant Professor of Neurology, University of Pennsylvania School of Medicine; Associate Neurologist, Pennsylvania Hospital, Philadelphia, Pa. JAMES L. ARMITAGE, M.D.: Assistant Professor of Neurology, University of Cincinnati; Chief, Neurology Service, Veterans Administration Hospital, Cincinnati, Ohio. 81
SCHUTTA
AND
ARMITAGE
Fig. l.-T-system is clearly visible in several areas (t). Terminal sacs of sarcoplasmic reticulum marked SR 3 and 4 are normal; SR 2, 6 and 7 are slightly enlarged; SR 1 and 5 are moderately enlarged in comparison to SR 3 and 4 X 60,000). Fig 2.-Large ovoid structures marked SR displace t tubule from its normal position at AI injunction. Membrane bounding structures is indistinct; contents is grammlar and appears similar to that in normal and slightly enlarged SR shown in Fig. 1 (X 50,000). uncommon. The T tubules were frequently displaced from their normal position at the A-I junction. Normal appearing triads were intermingled with the abnormal ones ( Figs. 1 and 2). Several investigations have shown that the sarcoplasmic reticulum accumulates calcium ions, and it appears that these are concentrated in the
SARCOPLASMIC
83
RETICULUM
terminal sacs of the SR.3-6 Since the material distending the terminal sacs of the sarcoplasmic reticulum is morphologically quite similar to that found in normal terminal sacs of SR, it is possible that these enlargements may be due to calcium accumulations. Exchange of calcium between the SR and the surrounding myofibrilles evidently plays an important part in the contraction and relaxation processes of muscle. 7,8 Our suggestion that excessive amounts of calcium may accumulate in the SR in thyrotoxic h.p.p. require confirmation. Further studies will show whether this is a universal finding in thyrototic h.p.p. and whether it also applies to familial h.p.p. An excessive accumulation of calcium ions would indicate a disturbance of calcium movements between the SR and the myofibrills, which would most certainly lead to the impairment of muscle function, i.e., paralysis. We believe that studies of muscle calcium metabolism might prove interesting in hypokalemic and possibly other types of periodic paralysis. REFERENCES 1. McArdle, B.: Familial periodic paralysis. Brit. Med. Bull. 12:226, 1956. 2. Shy, G. M., Wanko, T., Rowley, P. T., and Engel, A. G.: Studies in familial periodic paralysis. Exp. Neurol. 3:53, 1961. 3. Constantin, L. L., Franzini-Armstrong, C., and Podolsky, R. J.: Localization of calcium-accumulating structures in striated muscle. Science 147: 158, 1965. 4. Ebashi, S., and Lipman, F.: Adenosine triphosphate-linked concentration of calcium in a particulate fraction of rabbit muscle. J. Cell Biol. 14:389, 1962. 5. Hasselbach, W.: Relaxation and the
sarcotubular calcium pump. Fed. Proc. 23: 909,1964. 6. Martonosi, A., and Feretos, R.: Sarcoplasmic reticulum. I. The uptake of Ca++ by sarcoplasmic reticulum fragments. J. Biol. Chem. 239: 748,1964. 7. Frank, G.: Calcium and other divalent ions in the contraction of skeletal muscle. In Paul, W., Daniel, E. E., and Monckton, G. (Eds.): Muscle. New York, Pergamon Press, 1964, p. 155. 8. Heilburn, L. V., and Wiercinski, F. J.: Action of various cations on muscle protoplasm. J. Cell. Comp. Physiol. 29:15, 1947.