Marc E Tischler

Interests

Teaching

Medical Biochemistry, Nutrition and Endocrinology

Courses

Scholarly Contributions

Books

• Trowers, E. A., & Tischler, M. E. (2014). Gastrointestinal Physiology: A Clinical Approach. Springer.
• Tischler, M. E. (2012). Medical Biochemistry: The Big Picture. McGraw Hill.

Journals/Publications

• Tischler, M., Weinstein, R. B., Eleid, N., LeCesne, C., Durando, B., Crawford, J. T., Heffner, M., Layton, C., O'Keefe, M., Robinson, J., Rudinsky, S., Henriksen, E. J., & Tischler, M. E. (2002). Differential half-maximal effects of human insulin and its analogs for in situ glucose transport and protein synthesis in rat soleus muscle. Metabolism: clinical and experimental, 51(8).
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  Analogs of human insulin have been used to discriminate between responses of metabolic and mitogenic (growth-related) pathways. This study compared the stimulatory effects of human insulin (HI) and 2 analogs (X2, B-Asp(9), B-Glu(27) and H2, A-His(8),B-His(4),B-Glu(10), B-His(27)) on glucose uptake and protein synthesis in rat soleus muscle in situ. Glucose uptake, estimated by intramuscular (IM) injection of 2-deoxy[1,2-3H]glucose with or without insulin, was maximally increased at 10(-6) mol/L for HI and X2 and 10(-7) mol/L for H2. HI had a larger effect (318%) than either X2 (156%) or H2 (124%). The half-maximal effect (ED(50)) values for HI, X2, and H2 were 3.3 x10(-8) mol/L, 1.7 x 10(-7) mol/L, and 1.6 x 10(-9) mol/L, respectively. Protein synthesis, estimated by protein incorporation of [(3)H]phenylalanine injected into muscles with or without insulin, was maximally increased at 10(-5) mol/L for HI and 10(-6) for X2 and H2. HI had a larger effect in stimulating protein synthesis (34%) than either X2 (25%) or H2 (19.8%). The ED(50) values for HI, X2, and H2 were 3.0 x 10(-7) mol/L, 3.2 x 10(-7) mol/L, and 1.0 x 10(-9) mol/L, respectively. The biological potency of each analog (ED(50)insulin/ED(50)analog) showed X2 to be less potent than HI for both glucose uptake (0.2) and protein synthesis (0.9), whereas H2 is more potent than HI with ratios of 20 and 300, respectively. These data suggest that this approach for studying insulin responsiveness in a single muscle in situ may be a useful tool for investigating insulin signaling in muscle in vivo.
• Tischler, M., Weinstein, R. B., Slentz, M. J., Webster, K., Takeuchi, J. A., & Tischler, M. E. (1997). Lysosomal proteolysis in distally or proximally denervated rat soleus muscle. The American journal of physiology, 273(4 Pt 2).
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  We examined the mechanism of accelerated proteolysis in denervated rat soleus muscles. The soleus was denervated by severing either the tibial nerve (proximal, short stump) or sciatic nerve (distal, long stump) at 24, 48, 72, or 96 h before excision. Twenty-four hours after denervation, the extent of atrophy was similar for proximal and distal denervation, although lysosomal latency declined in both groups. After 48 and 72 h, denervation resulted in a decline in protein content, an increase in in vitro protein degradation, and a decline in lysosomal latency, all of which were greater in proximally denervated than in contralateral distally denervated muscles. These differences between acute responses of proximally and distally denervated muscles suggest the retention of some factor in the longer nerve stump that attenuates atrophy. After 96 h, total protein loss, protein degradation, and lysosomal latency were similar for proximal and distal denervation, suggesting the loss of axoplasmic flow from the long nerve stump.
• Tischler, M., Wu, M., & Tischler, M. E. (1995). Utilization of [14C]phenylalanine derived from arylphorin or free amino acid in Manduca sexta pharate adults. Archives of insect biochemistry and physiology, 28(3).
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  The role of arylphorin as a storage protein was studied using 14C-arylphorin. 14C-arylphorin was produced optimally by incubating one-half fat body from Manduca sexta fifth instar larvae at 22 degrees C for 24 h, in 1 ml of medium containing amino acids at 25% of their physiological concentration with [U-14C]-phenylalanine (phe) provided initially without nonlabeled phenylalanine. Nonlabeled phe was provided after 1 h at 16% of its physiological concentration. The specific activity of 14C-arylphorin produced in vitro was 30 times greater than that generated in vivo. Injection of 14C-arylphorin into pharate adults was used to study the distribution of 14C-phe derived from this protein into 14CO2 and tissues for comparison with injection of free 14C-phe during the middle (days 6 to 12 pharate adult) and late (days 12 to 17 pharate adult) stages of adult development. Appearance of 14CO2 from 14C-arylphorin as compared to 14C-phenylalanine showed a slower time course during both the middle and late stages of development, in keeping with the time needed for degradation of the protein. In accord with faster phe turnover near the end of adult development, total 14CO2 production was greater and the retention of 14C in hemolymph and fat body was less compared to the middle stage of development regardless of whether 14C-arylphorin or 14C-phe was injected. In the middle stage of development, the appearance of 14C in the cuticle and head parts was greater, whereas incorporation into abdomen and thorax was less than during the late stage of development. Since the pattern of 14C distribution from 14C-arylphorin and 14C-phe was similar, one major function of arylphorin must be as a storage protein replenishing the supply of free amino acids used for synthesis of adult tissues. These results also suggest a limited contribution of M. sexta arylphorin to formation of the cuticle subsequent to day-6 pharate adult.
• Tischler, M., & Tischler, M. E. (1994). Effect of the antiglucocorticoid RU38486 on protein metabolism in unweighted soleus muscle. Metabolism: clinical and experimental, 43(11).
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  Unweighting the hindlimbs by tail suspension of juvenile rats leads to atrophy of the soleus muscle, especially during the third day of unweighting. Although a previous study using adrenalectomized animals suggested a minimal role of glucocorticoids in this atrophy, the inability of adrenalectomized animals to release other adrenal hormones could have been important. Therefore, the influence of oral administration of RU38486 [11-beta-(4-dimethylaminophenyl) 17-beta-hydroxy 17-alpha(prop-1-ynyl) estra 4,9-dien 3-one], a selective glucocorticoid antagonist, on protein metabolism in the unweighted soleus was studied. The effectiveness of RU38486 treatment was demonstrated in hindlimb-suspended rats as the drug abolished the increase in soleus glutamine synthetase activity shown previously to be caused by elevated circulating glucocorticoids. The slower weight gain of suspended rats was unaffected by the drug. After 3 days of unweighting, the difference in protein content from weighted soleus muscle was not diminished significantly by RU38486 (-25%, vehicle only; -18%, RU38486-treated). However, in both weight-bearing and suspended animals, RU38486 seemed to promote protein accretion between days 2 and 3 of the experiment; ie, unweighted muscle seemed to lose less protein. All suspended animals showed slower (-58% to -64%) fractional in vivo rates of synthesis. RU38486 did not affect these percent differences in fractional protein synthesis after either 2 or 3 days of unweighting. The apparent improvement in protein balance likely resulted from a decline in protein degradation in both the weight-bearing (-26%) and unweighted (-35%) soleus.(ABSTRACT TRUNCATED AT 250 WORDS)
• Tischler, M., Henriksen, E. J., Munoz, K. A., Aannestad, A. T., & Tischler, M. E. (1994). Cardiac protein content and synthesis in vivo after voluntary running or head-down suspension. Journal of applied physiology (Bethesda, Md. : 1985), 76(6).
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  The adaptive responses of myocardial protein metabolism to chronic increases in work load were evaluated in juvenile female Sprague-Dawley rats. Rats were studied under four conditions: normal weight bearing (N), voluntary wheel running (WR) for < or = 4 wk, head-down-tilt suspension for 7 days (HS), or wheel running (2 or 3 wk) followed by 7 days of suspension (WR-HS). WR activity plateaued after 2 wk at 16 km/day and was maintained through week 4. WR did not affect normal whole body growth. Protein metabolism was studied by measuring heart protein content and in vivo fractional rate of protein synthesis with the [3H]phenylalanine "flooding dose" method. Two weeks of WR increased (P < 0.05) absolute heart protein content (22%) and protein synthesis (21%) relative to age-matched N group values. These differences in protein content and synthesis were maintained for > or = 4 wk. Rats failed to gain significant body weight during suspension. Heart protein content increased (P < 0.05) by 12% to 26% as did protein synthesis (14% to 22%) in HS compared with N group. In WR-HS group, cardiac protein content and protein synthesis were maintained at significantly elevated levels. These findings indicate that 1) high-volume WR by young rats provides a convenient noninvasive method for producing rapid and substantial cardiac hypertrophy, which results, at least in part, from enhanced cardiac protein synthesis; and 2) head-down suspension of sedentary juvenile rats leads to increased cardiac protein synthesis, which helps to increase cardiac protein content despite a lack of whole body growth.
• Tischler, M., Munoz, K. A., Satarug, S., & Tischler, M. E. (1993). Time course of the response of myofibrillar and sarcoplasmic protein metabolism to unweighting of the soleus muscle. Metabolism: clinical and experimental, 42(8).
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  Contributions of altered in vivo protein synthesis and degradation to unweighting atrophy of the soleus muscle in tail-suspended young female rats were analyzed daily for up to 6 days. Specific changes in myofibrillar and sarcoplasmic proteins were also evaluated to assess their contributions to the loss of total protein. Synthesis of myofibrillar and sarcoplasmic proteins was estimated by intramuscular (IM) injection and total protein by intraperitoneal (IP) injection of flooding doses of 3H-phenylalanine. Total protein loss was greatest during the first 3 days following suspension and was a consequence of the loss of myofibrillar rather than sarcoplasmic proteins. However, synthesis of total myofibrillar and sarcoplasmic proteins diminished in parallel beginning in the first 24 hours. Therefore sarcoplasmic proteins must be spared due to a decrease in their degradation. In contrast, myofibrillar protein degradation increased, thus explaining the elevated degradation of the total pool. Following 72 hours of suspension, protein synthesis remained low, but the rate of myofibrillar protein loss diminished, suggesting a slowing of degradation. These various results show (1) acute loss of protein during unweighting atrophy is a consequence of decreased synthesis and increased degradation of myofibrillar proteins, and (2) sarcoplasmic proteins are spared due to slower degradation, likely explaining the sparing of plasma membrane receptors. Based on other published data, we propose that the slowing of atrophy after the initial response may be attributed to an increased effect of insulin.
• Tischler, M., Kirby, C. R., Woodman, C. R., Woolridge, D., & Tischler, M. E. (1992). Cyclic adenosine monophosphate accumulation and beta-adrenergic binding in unweighted and denervated rat soleus muscle. Metabolism: clinical and experimental, 41(7).
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  Unweighting, but not denervation, of muscle reportedly "spares" insulin receptors, increasing insulin sensitivity. Unweighting also increases beta-adrenergic responses of carbohydrate metabolism. These differential characteristics were studied further by comparing cyclic adenosine monophosphate (cAMP) accumulation and beta-adrenergic binding in normal and 3-day unweighted or denervated soleus muscle. Submaximal amounts of isoproterenol, a beta-agonist, increased cAMP accumulation in vitro and in vivo (by intramuscular [IM] injection) to a greater degree (P less than .05) in unweighted muscles. Forskolin or maximal isoproterenol had similar in vitro effects in all muscles, suggesting increased beta-adrenergic sensitivity following unweighting. Increased sensitivity was confirmed by a greater receptor density (Bmax) for [125I]iodo-(-)-pindolol in particulate preparations of unweighted (420.10(-18) mol/mg muscle) than of control or denervated muscles (285.10(-18) mol/mg muscle). The three dissociation constant (Kd) values were similar (20.3 to 25.8 pmol/L). Total binding capacity (11.4 fmol/muscle) did not change during 3 days of unweighting, but diminished by 30% with denervation. This result illustrates the "sparing" and loss of receptors, respectively, in these two atrophy models. In diabetic animals, IM injection of insulin diminished cAMP accumulation in the presence of theophylline in unweighted muscle (-66% +/- 2%) more than in controls (-42% +/- 6%, P less than .001). These results show that insulin affects cAMP formation in muscle, and support a greater in vivo insulin response following unweighting atrophy. These various data support a role for lysosomal proteolysis in denervation, but not in unweighting, atrophy.
• Tischler, M., Munoz, K. A., & Tischler, M. E. (1991). The effect of a space food bar diet on body and muscle mass in normal and hind-limb suspended rats. Aviation, space, and environmental medicine, 62(9 Pt 1).
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  A food bar diet is used for rats in space flight. Since ground based studies have only been performed with the typical rat chow in dry pellet form, we tested whether the food bar diet allows normal growth and normal response of muscle protein content to unloading. These parameters were measured in normal and tail-cast hind limb suspended rats fed standard pellets or food bars. Body mass following 5 d of hind limb unloading was similar in bar-fed (97.9 +/- 4.8 g) and pellet-fed (92.6 +/- 3.4 g) animals (p greater than 0.05). In addition, gains in body mass were comparable between bar-fed (5.3 g/d) and pellet-fed (5.1 g/d) animals. Food bar consumption over 6 d increased from 10.5 to 12.0 g/d animal. During 5 d of hind limb suspension, food bar consumption increased from 13.2 +/- 1.4 to 19.1 +/- 1.4 g/d per animal. In agreement with previous studies, hind limb unloading reduced soleus muscle mass and protein content per 100 g body mass in both diet groups (p less than 0.05). Protein content per 100 g body mass was unchanged for the plantaris, extensor digitorum longus and tibialis anterior muscles during suspension in both diet groups. Rodent consumption of a food bar diet results in normal gains in body mass and muscle protein when compared to a standard pellet diet, and does not alter the atrophic response of skeletal muscle to unloading.
• Tischler, M., Kirby, C. R., & Tischler, M. E. (1990). Beta-adrenergic effects on carbohydrate metabolism in the unweighted rat soleus muscle. Journal of applied physiology (Bethesda, Md. : 1985), 69(6).
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  The effects of insulin on carbohydrate metabolism in atrophied rat soleus muscle are increased after unweighting by tail-cast suspension. This work has been extended by testing the effect of unweighting on the response of carbohydrate metabolism to isoproterenol, a beta-adrenergic agonist. Isoproterenol promoted glycogen degradation more in the unweighted than in the weight-bearing soleus but showed no differences in the extensor digitorum longus, which is unresponsive to hindlimb unweighting. In soleus muscles depleted of glycogen, to avoid varied inhibitory effects of glycogen on glycogen synthesis, isoproterenol inhibited this process more in the unweighted muscle. Isoproterenol did not have a greater inhibitory effect on net uptake of 2-deoxy-D[1,2-3H]glucose by the unweighted muscle. Measurements of intracellular 2-deoxy-[3H]glucose 6-phosphate and 3-O-methyl-D-[1-3H]glucose, which cannot be phosphorylated, showed that isoproterenol inhibited glucose phosphorylation but not transport. This effect could be explained by an increase of glucose 6-phosphate, an inhibitor of hexokinase. At 100 microU insulin/ml but not at a lower amount (10 microU/ml), isoproterenol inhibited hexose phosphorylation more in the control than in the unweighted muscle. This result may be explained by greater insulin antagonism in the unweighted muscle owing to increased insulin sensitivity. However, insulin antagonism of isoproterenol stimulation of glycogenolysis or inhibition of glycogenesis was not altered by unweighting. Therefore, for some aspects of carbohydrate metabolism, the unweighted muscle has an increased response to beta-adrenergic activation, just as this muscle shows increased responses to insulin.
• Tischler, M., Fagan, J. M., & Tischler, M. E. (1989). Effects of oxygen deprivation on incubated rat soleus muscle. Life sciences, 44(10).
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  Isolated soleus muscle deprived of oxygen produces more lactate and alanine than oxygen-supplied muscle. Oxygenated muscle synthesized glutamine, while anoxic muscle used this amino acid. Oxygen deprivation decreased adenine nucleotides leading to the efflux of nucleosides. Protein synthesis and degradation responded differently to anoxia. Synthesis almost completely ceased, while proteolysis increased. Therefore, protein degradation in soleus muscle is enhanced when energy supplies and oxygen tension are low.
• Tischler, M., Henriksen, E. J., Kirby, C. R., & Tischler, M. E. (1989). Glycogen supercompensation in rat soleus muscle during recovery from nonweight bearing. Journal of applied physiology (Bethesda, Md. : 1985), 66(6).
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  The time course of glycogen changes in soleus muscle recovering from 3 days of nonweight bearing by hindlimb suspension was investigated. Within 15 min and up to 2 h, muscle glycogen decreased. Coincidentally, muscle glucose 6-phosphate and the fractional activity of glycogen phosphorylase, measured at the fresh muscle concentrations of AMP, increased. Increased fractional activity of glycogen synthase during this time was likely the result of greater glucose 6-phosphate and decreased glycogen. From 2 to 4 h, when the synthase activity remained elevated and the phosphorylase activity declined, glycogen levels increased (glycogen supercompensation). A further increase of glycogen up to 24 h did not correlate with the enzyme activities. Between 24 and 72 h, glycogen decreased to control values, possibly initiated by high phosphorylase activity at 24 h. At 12 and 24 h, the inverse relationship between glycogen concentration and the synthase activity ratio was lost, indicating that reloading transiently uncoupled glycogen control of this enzyme. These data suggest that the activities of glycogen synthase and phosphorylase, when measured at physiological effector levels, likely provide the closest approximation to the actual enzyme activities in vivo. Measurements made in this way effectively explained the majority of the changes in the soleus glycogen content during recovery from nonweight bearing.
• Tischler, M., Jaspers, S. R., Henriksen, E. J., Satarug, S., & Tischler, M. E. (1989). Effects of stretching and disuse on amino acids in muscles of rat hind limbs. Metabolism: clinical and experimental, 38(4).
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  Effects of stretching on muscle amino acids were tested in unloaded soleus by casting the foot in dorsiflexion on one limb of tail-casted, hindquarter-suspended rats. For comparison with unloading, amino acids also were measured in shortened extensor digitorum longus (EDL) in the same casted limb and in denervated leg muscles. Concentrations of tyrosine and glutamate were lower, while aspartate, ammonia, and the ratio of glutamine to glutamate were greater in the stretched than in the freely moving, unloaded soleus, but stretched did not differ from weight-bearing, control muscle. Therefore, stretching the soleus muscle prevented changes in certain amino acids due to unloading. Aspartate, ammonia, glutamine, and the ratio of glutamine to glutamate were lower in the shortened EDL than in the freely moving muscle of the contralateral limb, or in the control muscle. When denervated, these leg muscles also showed lower aspartate, ammonia, and ratio of glutamine to glutamate relative to innervated muscles. Since muscle shortening or denervation produced amino acid changes that mimicked the effects of unloading on the soleus, these responses must reflect the effect of muscle disuse. These data suggested that lower ammonia might cause the lower ratio of glutamine to glutamate with disuse. Because the fresh muscle energy charge, one factor which controls AMP deaminase, generally was not affected by disuse, altered deamination of glutamate via glutamate dehydrogenase may explain the variations in muscle ammonia.(ABSTRACT TRUNCATED AT 250 WORDS)
• Tischler, M., Jaspers, S. R., Henriksen, E., Jacob, S., & Tischler, M. E. (1989). Metabolism of branched-chain amino acids in leg muscles from tail-cast suspended intact and adrenalectomized rats. Metabolism: clinical and experimental, 38(2).
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  Degradation of branched-chain amino acids was studied in muscles of unloaded hind limbs from rats subjected to six days of tail-cast suspension. The total production of 14CO2 from uniformly labeled 14C-leucine, isoleucine, or valine, and the fluxes through leucine aminotransferase and alpha-ketoisocaproate dehydrogenase, which were measured using L-1-14C-leucine, were generally greater in the soleus and extensor digitorum longus muscles of unloaded than of weight-bearing hind limbs. Adrenalectomy abolished any difference in flux through the aminotransferase, whereas the administration of cortisol to adrenalectomized animals restored the greater flux in the unloaded soleus muscle. Adrenalectomy partially diminished the greater flux through alpha-ketoisocaproate dehydrogenase in the unloaded soleus, whereas cortisol (2 mg/100 g body weight) treatment increased this difference. In the extensor digitorum longus, adrenalectomy abolished the differences in both enzyme fluxes due to hind limb suspension. In this muscle, cortisol treatment increased these fluxes to a similar extent in both weight-bearing and suspended, adrenalectomized animals so that the normal difference was not restored. These results suggest that leucine catabolism in hind limb muscles of suspended rats was influenced primarily by increased circulating glucocorticoid hormones, which are elevated twofold to fourfold in these animals.
• Tischler, M., Henriksen, E. J., & Tischler, M. E. (1988). Time course of the response of carbohydrate metabolism to unloading of the soleus. Metabolism: clinical and experimental, 37(3).
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  The time course of the response of carbohydrate metabolism to unloading was studied in the soleus muscle of rats subjected to tail-cast suspension. In the fresh soleus, just 12 hours of unloading led to higher concentrations of glycogen and lower activity ratios of both glycogen synthase and glycogen phosphorylase. These changes were still evident on day 3. This initial accumulation of glycogen was likely due to its decreased degradation in response to muscle disuse. Thereafter, the increased glycogen concentration apparently diminished the activity ratio of glycogen synthase, leading to a subsequent fall in the total glycogen content after day 1. After 24 hours of unloading, when no significant atrophy was detectable, there was no differential response to insulin for in vitro glucose metabolism. As reported for day 6 (reference 6), on day 3 the soleus atrophied significantly and displayed a greater sensitivity to insulin for most of these parameters compared to the weight-bearing control muscle. However, insulin sensitivity for glycogen synthesis was unchanged. These results showed that the increased sensitivity to insulin of the unloaded soleus is associated with the degree of muscle atrophy, likely due to an increased insulin binding capacity relative to muscle mass. This study also showed that insulin regulation of glucose uptake and of glycogen synthesis is affected differentially in the unloaded soleus muscle.
• Tischler, M., Jaspers, S. R., & Tischler, M. E. (1988). Insulin effect on amino acid uptake by unloaded rat hindlimb muscles. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et métabolisme, 20(2).
• Tischler, M., Jaspers, S. R., Fagan, J. M., Satarug, S., Cook, P. H., & Tischler, M. E. (1988). Effects of immobilization on rat hind limb muscles under non-weight-bearing conditions. Muscle & nerve, 11(5).
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  Dorsiflexion of one unloaded hind limb caused hypertrophy of the soleus relative to weight-bearing controls and faster growth of the plantaris and gastrocnemius muscles relative to the contralateral freely moving muscles. Unloading of the soleus muscle diminished primarily myofibrillar proteins whereas stretching increased all proteins. Stretching the soleus increased RNA, accelerated, especially, in vitro synthesis of sarcoplasmic proteins, and diminished in vitro proteolysis. Both in vivo and in vitro results showed slower synthesis and faster degradation in the freely moving than in the weight-bearing soleus muscle, faster synthesis and slower degradation in the stretched than in the freely moving soleus muscle, and faster degradation in the stretched than in the weight-bearing soleus muscle. Hence, stretching of the soleus muscle prevented changes in mass and protein metabolism produced by unloading. Shortening of the extensor digitorum longus muscle produced less muscle growth, slowed in vitro protein synthesis, and lowered RNA relative to the contralateral, freely moving muscle.
• Tischler, M. E. (1980). Is regulation of proteolysis associated with redox state changes in rat skeletal muscle?. Biochemical Journal, 192, 963-966.

Other Teaching Materials

• Tischler, M. E., & Cross, H. E. (2013. Hereditary Ocular Disease: a database of hereditary ocular diseases. University of Arizona.
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  This website contains a database of hereditary disorders with important ocular features. It is designed as a portal site containing summary clinical descriptions with links to additional online information. Each description of a medical condition is also linked to a page containing information written in nontechnical language for patients. Illustrations by Marc Tischler, PhDThis is a continuing project as new diseases are identified for inclusion