1,569 research outputs found
Treatment with selectin blocking antibodies after lengthening contractions of mouse muscle blunts neutrophil accumulation but does not reduce damage
Pâ and Eâselectins are expressed on the surface of endothelial cells and may contribute to neutrophil recruitment following injurious lengthening contractions of skeletal muscle. Blunting neutrophil, but not macrophage, accumulation after lengthening contractions may provide a therapeutic benefit as neutrophils exacerbate damage to muscle fibers, while macrophages promote repair. In this study, we tested the hypothesis that Pâ and Eâselectins contribute to neutrophil, but not macrophage, accumulation in muscles after contractionâinduced injury, and that reducing neutrophil accumulation by blocking the selectins would be sufficient to reduce damage to muscle fibers. To test our hypothesis, we treated mice with antibodies to block Pâ and Eâselectin function and assessed leukocyte accumulation and damage in muscles 2Â days after lengthening contractions. Treatment with P/Eâselectin blocking antibodies reduced neutrophil content by about half in muscles subjected to lengthening contractions. In spite of the reduction in neutrophil accumulation, we did not detect a decrease in damage 2Â days after lengthening contractions. We conclude that Pâ and/or Eâselectin contribute to the neutrophil accumulation associated with contractionâinduced muscle damage and that only a portion of the neutrophils that typically accumulate following injurious lengthening contractions is sufficient to induce muscle fiber damage and force deficits. Thus, therapeutic interventions based on blocking the selectins or other adhesion proteins will have to reduce neutrophil numbers by more than 50% in order to provide a benefit.In the present study, we tested the hypothesis that Pâ and Eâselectins contribute to neutrophil accumulation in muscles after contractionâinduced injury, and that reducing neutrophil accumulation by blocking the selectins would be sufficient to reduce damage to muscle fibers. Treatment with P/Eâselectin blocking antibodies reduced neutrophil content by about half in muscles subjected to lengthening contractions but did not decrease damage. We conclude that Pâ and/or Eâselectin contribute to the neutrophil accumulation associated with contractionâinduced muscle damage and that therapeutic interventions based on blocking the selectins will have to reduce neutrophil numbers by more than 50% in order to provide a benefit.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/117094/1/phy212667.pd
Maintenance of subsynaptic myonuclei number is not driven by neural input
The development and maintenance of neuromuscular junctions (NMJ) are supported by a specialized population of myonuclei that are referred to as the subsynaptic myonuclei (SSM). The relationship between the number of SSM and the integrity of the NMJ as well as the impact of a loss of innervation on SSM remain unclear. This study aimed to clarify these associations by simultaneously analyzing SSM counts and NMJ innervation status in three distinct mouse models of acute and chronic NMJ disruption. SSM were identified using fluorescent immunohistochemistry for Nesprin1 expression, which is highly enriched in SSM, along with anatomical location beneath the muscle fiber motor endplate. Acute denervation, induced by surgical nerve transection, did not affect SSM number after 7Â days. Additionally, no significant changes in SSM number were observed during normal aging or in mice with chronic oxidative stress (Sod1â/â). Both aging WT mice and Sod1â/â mice accumulated degenerating and denervated NMJ in skeletal muscle, but there was no correlation between innervation status of a given NMJ and SSM number in aged or Sod1â/â mice. These findings challenge the notion that a loss of SSM is a primary driver of NMJ degradation and leave open questions of the mechanisms that regulate SSM number as well as the physiological significance of the precise SSM number. Further investigations are required to define other properties of the SSM, such as transcriptional profiles and structural integrity, to better understand their role in NMJ maintenance
AGE-RELATED CHANGES IN THE STRUCTURE AND FUNCTION OF SKELETAL MUSCLES
1.â For animals of all ages, during activation of skeletal muscles and the subsequent contraction, the balance between the force developed by the muscle and the external load determines whether the muscle shortens, remains at fixed length (isometric) or is lengthened. With maximum activation, the force developed is least during shortening, intermediate when muscle length is fixed and greatest during lengthening contractions. During lengthening contractions, when force is high, muscles may be injured by the contractions. 2.â âFrailtyâ and âfailure to thriveâ are most frequently observed in elderly, physically inactive people. A âfrailâ person is defined as one of small stature, with muscles that are atrophied, weak and easily fatigued. The condition of âfailure to thriveâ is typified by a lack of response to well-designed programmes of nutrition and physical activity. 3.â With ageing, skeletal muscle atrophy in humans appears to be inevitable. A gradual loss of muscle fibres begins at approximately 50 years of age and continues such that by 80 years of age, approximately 50% of the fibres are lost from the limb muscles that have been studied. For both humans and rats, the observation that the timing and magnitude of the loss of motor units is similar to that for muscle fibres suggests that the mechanism responsible for the loss of fibres and the loss of whole motor units is the same. The degree of atrophy of the fibres that remain is largely dependent on the habitual level of physical activity of the individual. 4.â âMaster athletesâ maintain a high level of fitness throughout their lifespan. Even among master athletes, performance of marathon runners and weight lifters declines after approximately 40 years of age, with peak levels of performance decreased by approximately 50% by 80 years of age. The success of the master athletes and of previously sedentary elderly who undertake well-designed, carefully administered training programmes provide dramatic evidence that age-associated atrophy, weakness and fatigability can be slowed, but not halted.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75382/1/j.1440-1681.2007.04752.x.pd
Repeated bouts of aerobic exercise lead to reductions in skeletal muscle free radical generation and nuclear factor ÎB activation
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65978/1/jphysiol.2008.155382.pd
Sestrins are evolutionarily conserved mediators of exercise benefits.
Exercise is among the most effective interventions for age-associated mobility decline and metabolic dysregulation. Although long-term endurance exercise promotes insulin sensitivity and expands respiratory capacity, genetic components and pathways mediating the metabolic benefits of exercise have remained elusive. Here, we show that Sestrins, a family of evolutionarily conserved exercise-inducible proteins, are critical mediators of exercise benefits. In both fly and mouse models, genetic ablation of Sestrins prevents organisms from acquiring metabolic benefits of exercise and improving their endurance through training. Conversely, Sestrin upregulation mimics both molecular and physiological effects of exercise, suggesting that it could be a major effector of exercise metabolism. Among the various targets modulated by Sestrin in response to exercise, AKT and PGC1α are critical for the Sestrin effects in extending endurance. These results indicate that Sestrin is a key integrating factor that drives the benefits of chronic exercise to metabolism and physical endurance
Tibialis anterior muscles in mdx mice are highly susceptible to contraction-induced injury
Skeletal muscles of patients with Duchenne muscular dystrophy (DMD) and mdx mice lack dystrophin and are more susceptible to contraction-induced injury than control muscles. Our purpose was to develop an assay based on the high susceptibility to injury of limb muscles in mdx mice for use in evaluating therapeutic interventions. The assay involved two stretches of maximally activated tibialis anterior (TA) muscles in situ . Stretches of 40% strain relative to muscle fiber length were initiated from the plateau of isometric contractions. The magnitude of damage was assessed one minute later by the deficit in isometric force. At all ages (2â19 months), force deficits were four- to seven-fold higher for muscles in mdx compared with control mice. For control muscles, force deficits were unrelated to age, whereas force deficits increased dramatically for muscles in mdx mice after 8 months of age. The increase in susceptibility to injury of muscles from older mdx mice did not parallel similar adverse effects on muscle mass or force production. The in situ stretch protocol of TA muscles provides a valuable assay for investigations of the mechanisms of injury in dystrophic muscle and to test therapeutic interventions for reversing DMD.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43148/1/10974_2004_Article_390575.pd
17âα estradiol ameliorates ageâassociated sarcopenia and improves lateâlife physical function in male mice but not in females or castrated males
Pharmacological treatments can extend mouse lifespan, but lifespan effects often differ between sexes. 17âα estradiol (17aE2), a less feminizing structural isomer of 17âÎČ estradiol, produces lifespan extension only in male mice, suggesting a sexually dimorphic mechanism of lifespan regulation. We tested whether these antiâaging effects extend to anatomical and functional agingâimportant in lateâlife healthâand whether gonadally derived hormones control aging responses to 17aE2 in either sex. While 17aE2 started at 4 months of age diminishes body weight in both sexes during adulthood, in lateâlife 17aE2âtreated mice better maintain body weight. In 17aE2âtreated male mice, the higher body weight is associated with heavier skeletal muscles and larger muscle fibers compared with untreated mice during aging, while treated females have heavier subcutaneous fat. Maintenance of skeletal muscle in male mice is associated with improved grip strength and rotarod capacity at 25 months, in addition to higher levels of most amino acids in quadriceps muscle. We further show that sexâspecific responses to 17aE2âmetabolomic, structural, and functionalâare regulated by gonadal hormones in male mice. Castrated males have heavier quadriceps than intact males at 25 months, but do not respond to 17aE2, suggesting 17aE2 promotes an antiâaging skeletal muscle phenotype similar to castration. Finally, 17aE2 treatment benefits can be recapitulated in mice when treatment is started at 16 months, suggesting that 17aE2 may be able to improve aspects of lateâlife function even when started after middle age.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148386/1/acel12920_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148386/2/acel12920.pd
The development of a new measure of quality of life in the management of gastro-oesophageal reflux disease: the Reflux Questionnaire.
INTRODUCTION
This paper reports on the development of a new measure of health-related quality of life for use among patients with gastro-oesophageal reflux disease (GORD), funded as part of the REFLUX trial. This is a large UK multi centre trial that aims to compare the clinical and cost effectiveness of minimal access surgery with best medical treatment for patients with GORD within the NHS.
Method Potential items were identified via a series of interviews and focus groups carried out with patients who were receiving/had received medical or surgical treatment for GORD. The final measure consisted of 31 items covering 7 categories (Heartburn; Acid reflux; Wind; Eating and swallowing; Bowel movements; Sleep; Work, physical and social activities). The measure produced two outputs: a quality of life score (RQLS) and five Reflux symptom scores. Reliability (internal consistency), criterion validity with the SF-36 and, sensitivity to change in terms of relationship with reported change in prescribed medication were assessed amongst a sample of 794 patients recruited into the trial.
RESULTS
The measure was shown to be internally consistent, to show criterion validity with the SF-36 and sensitive to changes in patients use of prescribed medication at baseline and 3 month follow-up.
DISCUSSION
The Reflux questionnaire is a new self-administered questionnaire for use amongst patients with GORD. Initial findings suggest that the new measure is valid, reliable, acceptable to respondents and simple to administer in both a clinical and research context
Murine Fig4 is dispensable for muscle development but required for muscle function
Abstract
Background
Phosphatidylinositol phosphates (PIPs) are low-abundance phospholipids that participate in a range of cellular processes, including cell migration and membrane traffic. PIP levels and subcellular distribution are regulated by a series of lipid kinases and phosphatases. In skeletal muscle, PIPs and their enzymatic regulators serve critically important functions exemplified by mutations of the PIP phosphatase MTM1 in myotubular myopathy (MTM), a severe muscle disease characterized by impaired muscle structure and abnormal excitationâcontraction coupling. FIG4 functions as a PIP phosphatase that participates in both the synthesis and breakdown of phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2). Mutation of FIG4 results in a severe neurodegenerative disorder in mice and a progressive peripheral polyneuropathy in humans. The effect of FIG4 mutation on skeletal muscle has yet to be examined.
Methods
Herein we characterize the impact of FIG4 on skeletal muscle development and function using the spontaneously occurring mouse mutant pale tremor (plt), a mouse line with a loss of function mutation in Fig4.
Results
In plt mice, we characterized abnormalities in skeletal muscle, including reduced muscle size and specific force generation. We also uncovered ultrastructural abnormalities and increased programmed cell death. Conversely, we detected no structural or functional abnormalities to suggest impairment of excitationâcontraction coupling, a process previously shown to be influenced by PI(3,5)P2 levels. Conditional rescue of Fig4 mutation in neurons prevented overt muscle weakness and the development of obvious muscle abnormalities, suggesting that the changes observed in the plt mice were primarily related to denervation of skeletal muscle. On the basis of the ability of reduced FIG4 levels to rescue aspects of Mtmr2-dependent neuropathy, we evaluated the effect of Fig4 haploinsufficiency on the myopathy of Mtm1-knockout mice. Male mice with a compound Fig4
+/â/Mtm1
â/Y genotype displayed no improvements in muscle histology, muscle size or overall survival, indicating that FIG4 reduction does not ameliorate the Mtm1-knockout phenotype.
Conclusions
Overall, these data indicate that loss of Fig4 impairs skeletal muscle function but does not significantly affect its structural development.http://deepblue.lib.umich.edu/bitstream/2027.42/112676/1/13395_2013_Article_83.pd
Neuronâspecific expression of CuZnSOD prevents the loss of muscle mass and function that occurs in homozygous CuZnSODâknockout mice
Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154306/1/fsb2028004015.pd
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