scholarly journals Phrenic motor neuron loss in aged rats

2018 ◽  
Vol 119 (5) ◽  
pp. 1852-1862 ◽  
Author(s):  
Matthew J. Fogarty ◽  
Tanya S. Omar ◽  
Wen-Zhi Zhan ◽  
Carlos B. Mantilla ◽  
Gary C. Sieck
Keyword(s):  
Motor Neuron ◽  
Surface Area ◽  
Motor Neurons ◽  
Fiber Type ◽  
Dendritic Morphology ◽  
Diaphragm Muscle ◽  
Specific Force ◽  
Fischer 344 Rats ◽  
Fischer 344 ◽  
Age Related

Sarcopenia is the age-related reduction of muscle mass and specific force. In previous studies, we found that sarcopenia of the diaphragm muscle (DIAm) is evident by 24 mo of age in both rats and mice and is associated with selective atrophy of type IIx and IIb muscle fibers and a decrease in maximum specific force. These fiber type-specific effects of sarcopenia resemble those induced by DIAm denervation, leading us to hypothesize that sarcopenia is due to an age-related loss of phrenic motor neurons (PhMNs). To address this hypothesis, we determined the number of PhMNs in young (6 mo old) and old (24 mo old) Fischer 344 rats. Moreover, we determined age-related changes in the size of PhMNs, since larger PhMNs innervate type IIx and IIb DIAm fibers. The PhMN pool was retrogradely labeled and imaged with confocal microscopy to assess the number of PhMNs and the morphometry of PhMN soma and proximal dendrites. In older animals, there were 22% fewer PhMNs, a 19% decrease in somal surface area, and a 21% decrease in dendritic surface area compared with young Fischer 344 rats. The age-associated loss of PhMNs involved predominantly larger PhMNs. These results are consistent with an age-related denervation of larger, more fatigable DIAm motor units, which are required primarily for high-force airway clearance behaviors. NEW & NOTEWORTHY Diaphragm muscle sarcopenia in rodent models is well described in the literature; however, the relationship between sarcopenia and frank phrenic motor neuron (MN) loss is unexplored in these models. We quantify a 22% loss of phrenic MNs in old (24 mo) compared with young (6 mo) Fischer 344 rats. We also report reductions in phrenic MN somal and proximal dendritic morphology that relate to decreased MN heterogeneity in old compared with young Fischer 344 rats.

Age-related increases in diaphragmatic maximal shortening velocity

1996 ◽  
Vol 80 (2) ◽  
pp. 445-451 ◽  
Author(s):  
S. K. Powers ◽  
D. Criswell ◽  
R. A. Herb ◽  
H. Demirel ◽  
S. Dodd
Keyword(s):  
Force Production ◽  
Specific Force ◽  
Fischer 344 Rats ◽  
Rat Diaphragm ◽  
Shortening Velocity ◽  
Fischer 344 ◽  
Age Related ◽  
Highly Correlated ◽  
Related Increase

Recent evidence demonstrates that aging results in an increase in fast (type IIB) myosin heavy chain (MHC) in the rat diaphragm. It is unknown whether this age-related change in fast MHC influences the diaphragmatic maximal shortening velocity (Vmax). Therefore, we tested the hypothesis that aging is associated with an increase in the diaphragmatic Vmax and that the increase in the Vmax is highly correlated with the percentage of type IIb MHC. In vitro contractile properties were measured with costal diaphragm strips obtained from young (4 mo old; n = 8) and (old 24 mo old; n = 8) male Fischer-344 rats. Diaphragmatic maximal tetanic specific force production was 14.5% lower in the old compared with the young animals (23.0 +/- 0.4 vs. 19.7 +/- 0.8 N/cm2; P < 0.05). In contrast, the diaphragmatic Vmax was significantly higher in the old compared with the young animals (5.5 +/- 0.1 vs. 4.4 +/- 0.3 lengths/s; P < 0.05). Although the percent type IIb MHC was significantly higher (approximately +14%; P < 0.05) in the old compared with the young animals, the correlation between Vmax and percent type IIb MHC was relatively low (r = 0.50; P = 0.05). These data support the hypothesis that an age-related increase in diaphragmatic Vmax occurs; however, factors in addition to type IIb MHC are involved in regulating diaphragmatic Vmax. Interestingly, although aging resulted in a decrease in diaphragmatic maximal specific force production, power output at all muscle loads was maintained in the old animals due to the increase in diaphragmatic shortening velocity.

Upregulation of G protein-linked receptor kinases with advancing age in rat aorta

2001 ◽  
Vol 280 (3) ◽  
pp. R897-R903 ◽  
Author(s):  
William E. Schutzer ◽  
John F. Reed ◽  
Michael Bliziotes ◽  
Scott L. Mader
Keyword(s):  
G Protein ◽  
Rat Aorta ◽  
Aortic Tissue ◽  
Fischer 344 Rats ◽  
Membrane Expression ◽  
Fischer 344 ◽  
Age Related ◽  
Protein Receptor ◽  
Receptor Kinases ◽  
Increased Activity

The age-related decline in β-adrenergic receptor (β-AR)-mediated vasorelaxation is associated with desensitization of β-ARs without significant downregulation. The primary mode of this homologous β-AR desensitization, in general, is via G protein receptor kinases (GRK). Therefore, we hypothesize that age-related changes in GRKs are causative to this etiology in rat aorta. Herein, we investigate the activity and cellular distribution (cytoplasmic vs. membrane) of several GRK isoforms and β-arrestin proteins. GRK activity was assessed in extracts from aortic tissue of 6-wk, 6-mo, 12-mo, and 24-mo-old male Fischer-344 rats using a rhodopsin phosphorylation assay. We also performed immunoblots on lysates from aorta with specific antibodies to GRK-2, -3, -5, and β-arrestin-1. Results show an age-related increase in GRK activity. Furthermore, expression of GRK-2 (cytoplasmic and membrane), GRK-3 (cytoplasmic and membrane), and β-arrestin (soluble) increased with advancing age, whereas GRK-5 (membrane) expression remained unchanged. These results suggest that age is associated with increased activity and expression of specific GRKs. This increase likely results in enhanced phosphorylation and desensitization of β-ARs. These biochemical changes are consistent with observed aging physiology.

scholarly journals Interactive effects of denervation and malnutrition on diaphragm structure and function

1996 ◽  
Vol 81 (5) ◽  
pp. 2165-2172 ◽  
Author(s):  
Michael I. Lewis ◽  
Thomas J. Lorusso ◽  
Wen-Zhi Zhan ◽  
Gary C. Sieck
Keyword(s):  
Fiber Type ◽  
Structure And Function ◽  
Interactive Effects ◽  
Diaphragm Muscle ◽  
Fiber Types ◽  
Specific Force ◽  
Cross Sectional ◽  
Total Cross Sectional Area ◽  
Generating Capacity ◽  
And Function

Lewis, Michael I., Thomas J. Lorusso, Wen-Zhi Zhan, and Gary C. Sieck. Interactive effects of denervation and malnutrition on diaphragm structure and function. J. Appl. Physiol. 81(5): 2165–2172, 1996.—The purpose of this study was to examine the interactive effects of unilateral denervation (DN) and prolonged malnutrition (MN) on the structure and function of the diaphragm muscle (Dia). Four groups of rats were studied: control (Con), MN, DN, and DN-MN. MN began 2 wk after DN and lasted 4 wk. In both the DN and DN-MN groups, the relative loss in Dia weight exceeded the relative change in body weight. Compared with the Con group, Dia specific force was reduced by ∼40% in both the DN and DN-MN groups but was unaffected in the MN group. Dia fatigue resistance improved in all experimental groups but to a greater extent in the DN and DN-MN groups. In both the DN and DN-MN groups, ∼50% of Dia fibers were classified as type IIc, whereas fiber type proportions did not change in the MN group. In the DN group, only type IIb/x fibers atrophied, whereas all fiber types atrophied in the MN and DN-MN groups. We conclude that in the DN-MN group the reduction in specific force combined with the reduction in total cross-sectional area of the muscle significantly curtails Dia force-generating capacity.

scholarly journals Induction of G1 checkpoint in the gastric mucosa of aged rats

1999 ◽  
Vol 277 (5) ◽  
pp. G929-G934 ◽  
Author(s):  
Zhi-Qiang Xiao ◽  
Yingjie Yu ◽  
Ahmed Khan ◽  
Richard Jaszewski ◽  
Murray N. Ehrinpreis ◽  
...  
Keyword(s):  
Gastric Mucosa ◽  
Proliferative Activity ◽  
Protein A ◽  
S Phase ◽  
Aged Rats ◽  
Fischer 344 Rats ◽  
Protein Levels ◽  
Fischer 344 ◽  
Age Related ◽  
P53 Status

Although in Fischer 344 rats aging is found to be associated with increased gastric mucosal proliferative activity, little is known about specific changes in the regulatory mechanisms of this process. To determine whether changes in cell cycling events could partly contribute to the age-related rise in gastric mucosal proliferative activity, the present investigation examines changes in cyclin-dependent kinase (Cdk2) activity and the regulation of this process in the gastric mucosa of Fischer 344 rats aged 4 (young), 13 (middle aged), and 24 (old) mo. We observed that aging is associated with a progressive rise in activity and protein levels of Cdk2 in the gastric mucosa. This is also found to be accompanied by a concomitant increase in cyclin E but not cyclin D1 levels. On the other hand, the levels of p21Waf1/Cip1 (total as well as the fraction associated with Cdk2), a nuclear protein that is known to inhibit different cyclin-Cdk complexes, are found to decline in the gastric mucosa with advancing age. In contrast, with aging, there was a steady rise in p53 levels in the gastric mucosa. We have also observed that the levels of phosphorylated retinoblastoma protein, a form that participates in regulating progression through the S phase, are markedly elevated in the gastric mucosa of aged rats. In conclusion, our data suggest that, in the gastric mucosa, aging enhances transition of G1 to S phase as well as progression through the S phase of the cell cycle. However, the age-related decline in p21Waf1/Cip1 in the gastric mucosa appears to be independent of p53 status.

scholarly journals Diaphragm muscle function following midcervical contusion injury in rats

2019 ◽  
Vol 126 (1) ◽  
pp. 221-230 ◽  
Author(s):  
Obaid U. Khurram ◽  
Matthew J. Fogarty ◽  
Sabhya Rana ◽  
Pangdra Vang ◽  
Gary C. Sieck ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Force Generation ◽  
Diaphragm Muscle ◽  
Neuron Loss ◽  
Motor Behaviors ◽  
Contusion Injury ◽  
Motor Neuron Loss ◽  
The Impact ◽  
Over Time

Midcervical spinal cord contusion injury results in tissue damage, disruption of spinal pathways, and motor neuron loss. Unilateral C4 contusion results in loss of 40%–50% of phrenic motor neurons ipsilateral to the injury (~25% of the total phrenic motor neuron pool). Over time after unilateral C4 contusion injury, diaphragm muscle (DIAm) electromyogram activity increases both contralateral and ipsilateral to the side of injury in rats, suggesting compensation because of increased activation of the surviving motor neurons. However, the impact of contusion injury on DIAm force generation is less clear. Transdiaphragmatic pressure (Pdi) was measured across motor behaviors over time after unilateral C4 contusion injury in adult male Sprague-Dawley rats. Maximum Pdi (Pdimax) was elicited by bilateral phrenic nerve stimulation at 7 days postinjury. We hypothesized that Pdimax is reduced following unilateral C4 contusion injury, whereas ventilatory behaviors of the DIAm are unimpaired. In support of our hypothesis, Pdimax was reduced by ~25% after unilateral C4 contusion, consistent with the extent of phrenic motor neuron loss following contusion injury. One day after contusion injury, the Pdi amplitude during airway occlusion was reduced from ~30 to ~20 cmH2O, but this reduction was completely reversed by 7 days postinjury. Ventilatory behaviors (~10 cmH2O), DIAm-specific force, and muscle fiber cross-sectional area did not differ between the laminectomy and contusion groups. These results indicate that the large reserve capacity for DIAm force generation allows for higher-force motor behaviors to be accomplished despite motor neuron loss, likely reflecting changes in motor unit recruitment. NEW & NOTEWORTHY Respiratory muscles such as the diaphragm generate the pressures necessary to accomplish a variety of motor behaviors ranging from ventilation to near-maximal expulsive behaviors. However, the impact of contusion injury on diaphragm pressure generation across behaviors is not clear. The present study shows that contusion injury impairs maximal pressure generation while preserving the ability of the diaphragm to accomplish lower-force motor behaviors, likely reflecting changes in diaphragm motor unit recruitment.

Age-related immunosenescence in Fischer 344 rats: influence of exercise training

1992 ◽  
Vol 73 (5) ◽  
pp. 1932-1938 ◽  
Author(s):  
I. Nasrullah ◽  
R. S. Mazzeo
Keyword(s):  
Endurance Training ◽  
Interleukin 2 ◽  
Cytolytic Activity ◽  
Treadmill Running ◽  
Target Cells ◽  
Fischer 344 Rats ◽  
Middle Aged ◽  
Fischer 344 ◽  
Age Related ◽  
Old Rats

The present investigation examined the extent to which 15 wk of endurance training could influence immune function in young, middle-aged, and older animals. Forty-eight male Fischer 344 rats were divided into trained and untrained groups. Training consisted of treadmill running at 75% maximal running capacity for 1 h/day, 5 days/wk, for 15 wk. Animals were killed at 8, 17, and 27 mo, at which time splenocytes were isolated. The capacity for lymphocyte proliferation in response to mitogen (concanavalin A, ConA), interleukin-2 (IL-2) production, and cytolytic activity against YAC-1 target cells was determined. ConA-induced proliferation declined significantly with age. Training suppressed the proliferative response in the young (-41%) and middle-aged animals (-27%) compared with the age-matched controls; however, training improved this response (+58%) in the older group. IL-2 production followed a pattern similar to that for mitogen-induced proliferation, such that production declined with age and was reduced with training in young and middle-aged animals but was significantly more improved in the older animals than in age-matched controls. The ability to lyse target cells, measured as percent cytotoxicity, declined steadily with advancing age at all effector-to-target cell ratios tested: 52, 14, and -16% for 8-, 17-, and 27-mo-old rats, respectively. It was concluded that the capacity for ConA-induced splenocyte proliferation, IL-2 production, and cytolytic activity declines significantly with advancing age. Furthermore, 15 wk of endurance training suppressed proliferation and IL-2 production in young animals but improved these responses in older animals. Training had no effect on cytolytic activity.

An age-related difference in hyperoxia lethality: role of lung antioxidant defense mechanisms

1995 ◽  
Vol 268 (4) ◽  
pp. L539-L545 ◽  
Author(s):  
A. T. Canada ◽  
L. A. Herman ◽  
S. L. Young
Keyword(s):  
Defense Mechanisms ◽  
Antioxidant Defense ◽  
Fischer 344 Rats ◽  
Fischer 344 ◽  
Related Difference ◽  
Age Related ◽  
65 H ◽  
Old Rats ◽  
Gpx Activity

The role of animal age in the lethal response to > 98% oxygen has been extensively studied, with the observation that neonatal rats were resistant while mature animals were sensitive. Antioxidant enzymes increased during the oxygen exposure in neonatal but not in mature rats, suggesting they were important in the age-related toxicity difference. Because no studies had compared the response of mature and old rats to hyperoxia, we exposed Fischer 344 rats, aged 2 and 27 mo, to > 98% oxygen. Unexpectedly, the old rats lived significantly longer than young, 114 and 65 h, respectively. No histopathological differences were found to explain the results. Of the antioxidants, only glutathione peroxidase (GPx) activity was higher in the lungs of nonexposed old rats. Superoxide dismutase (SOD) was higher in the young, results opposite those expected if SOD was important in the lethality difference. No antioxidant induction occurred in the old oxygen-exposed rats. These results suggest that although there may be a role for GPx, mechanisms in addition to antioxidant protection and inflammation are likely responsible for the age-related difference in hyperoxia lethality.

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