Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1762617 (weakness)
 37,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To extend our evaluation of insulin-like growth factor-1 (IGF-1) treatment for human demyelinating diseases, we compared effects of s.c. and i.v. IGF-1 in an in vivo model with lesions resembling those seen in multiple sclerosis. Experimental autoimmune encephalomyelitis (EAE) was induced in Lewis rats with an emulsion containing guinea pig spinal cord and treatment with placebo or with s.c. or i.v. IGF-1 was started when definite clinical weakness was present. IGF-I given subcutaneously significantly reduced clinical deficits and lesion severity. The clinical improvement, as measured by clinical deficit scores, stride lengths and exercise wheel rotations, was evident in 48 hrs and was comparable to that produced by the same IGF-I dose administered intravenously. Subcutaneously administered IGF-I also increased relative mRNA levels of myelin basic protein (MBP), proteolipid (PLP) and 2',3' cyclic nucleotide 3'-phosphodiesterase (CNP), thereby promoting myelin regeneration. We conclude that s.c. IGF-I produces dramatic improvement in acute, demyelinating EAE. Our results also suggest that this growth factor may be useful in treating multiple sclerosis patients with active demyelination.
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PMID:Insulin-like growth factor-I given subcutaneously reduces clinical deficits, decreases lesion severity and upregulates synthesis of myelin proteins in experimental autoimmune encephalomyelitis. 861 86

Our previous study in vivo suggested that vascular smooth muscle cells (VSMCs) in stroke-prone spontaneously hypertensive rats (SHRSP) were vulnerable when plasma components were deficient. Therefore, we cultured VSMCs isolated from normotensive and hypertensive rats to clarify the weakness of VSMCs isolated from hypertensive rats and maintained in plasma-deficient conditions by employing ultrastructural and biochemical analyses. VSMCs, obtained from normotensive rats and cultured without fetal bovine serum (FBS) for 1 week, were intact and well differentiated; without FBS for 2 weeks retained their original structures except for several degenerative changes. VSMCs, obtained from hypertensive rats and cultured without FBS for 2 weeks, were extensively damaged and lost their cell organelles. Apoptotic bodies were frequently observed. We also cultured VSMCs in medium containing a variety of growth factors. VSMCs obtained from normotensive rats and cultured with epidermal growth factor or insulin-like growth factor-1 for 2 weeks were almost intact, as were VSMCs from hypertensive rats, although some degenerative changes of cell organelles were observed. VSMCs from hypertensive rats, maintained with platelet-derived growth factor-BB or basic fibroblast growth factor, were generally in poor condition. Thus VSMCs from hypertensive rats have hereditary weaknesses in cell survival including apoptosis and require specific growth factors for their maintenance.
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PMID:Ultrastructural analysis of survival in cultured smooth muscle cells isolated from stroke-prone spontaneously hypertensive rats: effect of growth factors. 876 57

Myogenic satellite cell clones were established from the pectoralis major muscle of chickens with the low score normal (LSN) muscle weakness and controls. The percentage of cells which attached to substrata and began to proliferate was higher for the control line than the LSN line (55% vs 30%). Furthermore, of those clones which initiated growth, 63% of the control cells and only 32% of the LSN cells proliferated to confluence in 25 cm2 tissue culture flasks. Proliferation rates were significantly lower with LSN satellite cells than with controls (p < 0.05). LSN satellite cells were less responsive to the mitogenic effects of chicken serum (p < 0.05) and differentiation rates were lower compared with controls (p < 0.05). There was a greater (p < 0.05) number of insulin-like growth factor receptors on LSN satellite cells compared with controls. The IGF receptor binding affinities (Kds) between the two cell lines were similar (p > 0.05). The results suggest that a defect in satellite cell physiology may contribute to the skeletal muscle weakness seen in the LSN line.
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PMID:Characterization of satellite cells derived from chickens with the low score normal (LSN) muscle weakness. 958 4

Excitation-contraction uncoupling has been identified as a mechanism underlying skeletal muscle weakness in aging mammals (sarcopenia). The basic mechanism for excitation-contraction uncoupling is a larger number of ryanodine receptors (RyR1) uncoupled to dihydropyridine receptors (DHPRs) (Delbono, O., O'Rourke, K. S., and Ettinger, W. H. (1995) J. Membr. Biol. 148, 211-222). In the present study, we used transgenic mice overexpressing human insulin-like growth factor-1 exclusively in skeletal muscle to test the hypothesis that a high concentration of IGF-1 prevents age-related decreases in DHPR number and in muscle force. Transgenic mice express 10-20-fold higher IGF-1 concentrations than nontransgenic mice at all ages (1-24 months). The number of DHPRs is 50-100% higher, and the DHPR/RyR1 ratio is 40% higher in transgenic soleus (predominantly type I fiber muscles), extensor digitorum longus (predominantly type II fiber muscles), and the pool of type I and type II fiber muscles than in nontransgenic young (6 months), adult (12 months), and old (24 months) mice. Furthermore, no age-related changes in DHPRs and the DHPR/RyR1 ratio were observed in transgenic muscles. The specific single twitch and tetanic muscle force in old transgenic soleus and extensor digitorum longus muscles are 50% higher than in old nontransgenic muscles. Taken together, these results support the concept that IGF-1- dependent prevention of age-related decline in DHPR expression is associated with stronger muscle contraction in older transgenic mice.
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PMID:Overexpression of IGF-1 exclusively in skeletal muscle prevents age-related decline in the number of dihydropyridine receptors. 978 85

In Duchenne muscular dystrophy (DMD), short stature is a feature of unknown cause. This cross-sectional study of 34 male patients (mean age 8.0 y, age range 1.2-13.7 y) was conducted to examine the relationship between auxological parameters, markers of growth and the extent of muscular weakness. Weight and length at birth (SDS +/- SD; 0.0 +/- 1.2; 0.2 +/- 1.5) and target height SDS (-0.2 +/- 0.7) were normal. Height (HT) SDS (-1.0 +/- 1.1) was lower than the normal population (p < 0.001) and did not correlate with age. Body mass index SDS (-0.1 +/- 1.6) was normal. Tests of insulin-like growth factor-I SDS (-0.6 +/- 1.2) and insulin-like growth factor binding protein-3 SDS (0.1 +/- 1.3) ruled out a severe derangement in the GH-IGF-axis. The carboxy-terminal propeptide of type I procollagen (PICP) SDS (0.6 +/- 1.5) was normal, but bone-specific alkaline phosphatase (BAP) SDS (-1.7 +/- 0.8) was low (p <0.001). HT SDS did not correlate with BAP SDS. The Vignos scale, a grading of muscular function (score: 0 = unaffected; 11 = confined to bed) (median (range): 3 (0-9)) correlated strongly with age (r = 0.77, p < 0.0001), but did not correlate with HT SDS, PICP SDS or BAP SDS. In conclusion, DMD patients are significantly shorter than the normal population, though the HT SDS does not change with age. Growth hormone deficiency does not seem to be the cause of short stature in DMD. Significantly low BAP levels are probably the result of the reduced muscle mass, which leads to a lower biomechanical load on the bone and thus a reduction in bone turnover. The short stature observed in our study is unlikely to be the result of muscular weakness.
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PMID:Short stature in Duchenne muscular dystrophy: a study of 34 patients. 1009 May 50

Frailty is characterized by generalized weakness, impaired mobility and balance, and poor endurance. Loss of muscle strength is an important factor in the process of frailty, and is the limiting factor for an individual's chances of living an independent life until death. In men, several hormonal systems show a decline in activity during aging. Serum bioavailable testosterone (T) and estradiol (E2), dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), and growth hormone (GH) and insulin-like growth factor (IGF)-I concentrations all decrease during aging in men. Physical changes during aging have been considered physiologic, but there is evidence that some of these changes are related to this decline in hormonal activity. In a cross-sectional study performed among 403 independently living elderly men, positive independent associations were observed between serum bioavailable T and muscle strength and bone mineral density (BMD). Serum T was negatively associated with fat mass. Serum luteinizing hormone (LH) increased with age and was inversely associated with T. Independent of T, LH was negatively related with muscle strength and positively with the number of problems in activities of daily living. Further, a positive relation was present between serum E2 and BMD. A positive association between DHEAS and BMD was dependent on T and E2 concentrations. Finally, in the same study, men with the highest E2 concentrations were significantly more satisfied with life, measured with a questionnaire developed by Herschbach and Huber, compared to men with the lowest E2 concentrations. In conclusion, these findings are in agreement with other studies, which suggest that the maintenance of a good physical functional ability and quality of life is related to serum T, E2, and DHEA(S) concentrations.
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PMID:The male climacterium: clinical signs and symptoms of a changing endocrine environment. 1105 86

Glucocorticoids have been widely used in the treatment of autoimmune and other diseases. Chronic steroid use, however, could cause proximal muscle weakness and atrophy, termed steroid myopathy. The onset of steroid myopathy is usually insidious and there are no specific laboratory findings except for elevated urinary creatine excretion. Muscle biopsy reveals non-specific type II fiber atrophy. There are many reports showing preventive effects of either growth hormone (GH) or insulin-like growth factor (IGF)-I on steroid myopathy. The pathogenesis of steroid myopathy is not fully understood. Recently, glutamine synthetase has been reported to play a key role in steroid myopathy. GH as well as IGF-I decreased the steroid-induced glutamine synthetase activity in skeletal muscle.
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PMID:Steroid myopathy: pathogenesis and effects of growth hormone and insulin-like growth factor-I administration. 1178 81

The symptomatic pharmacological therapy of Duchenne dystrophy is poor, glucocorticoids being the sole compounds showing a certain efficacy, although their use is restricted by serious side effects. Pre-clinical trials of prompt-to-use drugs need reliable animal models of the human disease to predict drug effectiveness in patients. The exercised mdx mouse develops a typical pattern of muscle weakness in vivo, which has already been used as an index on which to evaluate drug effectiveness. We have demonstrated that the macroscopic conductance to chloride ion, an index of degeneration-regeneration events occurring in mdx mouse muscles, is specifically impaired by a chronic exercise protocol and is sensitive to the action of in vivo administered drugs acting either by stimulating regeneration (insulin-like growth factor-1 and steroids) or by counteracting calcium-induced degeneration or inflammation (Taurine and steroids). The monitoring of conductance to chloride ion also allows the evaluation of false positive compounds, effective on mouse strength in vivo but not at muscle level, and the functional correlation with other cellular parameters.
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PMID:Pre-clinical trials in Duchenne dystrophy: what animal models can tell us about potential drug effectiveness. 1220 8

Sepsis, excessive inflammation, multiple organ failure and weakness prolong the need for intensive care in critically ill patients. Furthermore, the risk of death is high in the prolonged critically ill patient (20% after two weeks and 30% after 3 weeks). In prolonged critical illness, protein hypercatabolism and relative preservation of adipose tissue with fatty infiltration of vital organ systems is present. In view of the crucial role of the hypothalamus-pituitary axis for metabolic homeostasis, we have studied this endocrine organ in the context of critical illness. The initial "adaptive" neuroendocrine response to critical illness illness consists primarily of activated anterior pituitary function. In the chronic phase of critical illness, a uniformly reduced pulsatile secretion of anterior pituitary hormones has been observed, whereby impaired function of target organs. A reduced availability of thyrotropin (TSH)-releasing hormone (TRH), gonadotropin (LH)-releasing hormone (GnRH), the endogenous ligand of the growth hormone (GH)-releasing peptide (GHRP) receptor (ghrelin) and, in very long-stay critically ill men also of GH-releasing hormone (GHRH), inferrentially appears involved. Pulsatile secretion of GH, TSH and LH can be re-amplified by relevant combinations of releasing factors which also substantially increases circulating levels of insulin-like growth factor (IGF)-I, GH-dependent IGF-binding proteins, thyroxine (T4), triiodothyronine (T3) and testosterone. Anabolism is only evoked when GH-secretagogues, TRH and GnRH are administered together whereas the effect of single hormone treatment is minor and accompanied by side effects. A remarkable observation was that a high serum concentration of IGF-binding protein 1 predicts death in the ICU. This observation challenged the classical dogma of adaptive hyperglycemia during critical illness. In a large prospective randomized clinical study (1548 patients), we showed that ICU mortality was reduced by 42% with strict normalization of glycemia using exogenous insulin infusion (N Engl J Med 2001). This was due to prevention of typical ICU complications such as sepsis, multiple organ failure and need for prolonged invasive organ support and intensive care. We conclude that the new concept of reduced stimulation of pituitary function in prolonged critically ill patients opens new therapeutic perspectives to reverse the paradoxical 'wasting syndrome' but that maintenance of strict normoglycemia with insulin is crucial to also increase the chances of survival of these patients.
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PMID:Endocrinology in intensive care medicine: new insights and therapeutic consequences. 1223 41

A preclinical screening for prompt-to-use drugs that are safer than steroids and beneficial in Duchenne muscular dystrophy was performed. Compounds able to reduce calcium-induced degeneration (taurine or creatine 10% in chow) or to stimulate regeneration [insulin-like growth factor-1 (IGF-1); 50 or 500 microg/kg s.c.] were administered for 4 to 8 weeks to mdx mice undergoing chronic exercise on a treadmill, a protocol to worsen dystrophy progression. alpha-Methyl-prednisolone (PDN; 1 mg/kg) was used as positive control. The effects were evaluated in vivo on forelimb strength and in vitro electrophysiologically on the macroscopic chloride conductance (gCl), an index of degeneration-regeneration events in mdx muscles, and on the mechanical threshold, a calcium-sensitive index of excitation-contraction coupling. The exercise produced a significant weakness and an impairment of gCl, by further decreasing the already low value of degenerating diaphragm (DIA) and fully hampering the increase of gCl typical of regenerating extensor digitorum longus (EDL) mdx muscle. The already negative voltage threshold for contraction of mdx EDL was also slightly worsened. Taurine > creatine > IGF-1 counteracted the exercise-induced weakness. The amelioration of gCl was drug- and muscle-specific: taurine was effective in EDL, but not in DIA muscle; IGF-1 and PDN were fully restorative in both muscles, whereas creatine was ineffective. An acute effect of IGF-1 on gCl was observed in vitro in untreated, but not in IGF-1-treated exercised mdx muscles. Taurine > PDN > IGF-1, but not creatine, significantly ameliorated the negative threshold voltage values of the EDL fibers. The results predict a potential benefit of taurine and IGF-1 for treating human dystrophy.
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PMID:Enhanced dystrophic progression in mdx mice by exercise and beneficial effects of taurine and insulin-like growth factor-1. 1249 Jun 22


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