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Targeting Heat Shock Proteins Mitigates Ventilator Induced Diaphragm Muscle Dysfunction in an Age-Dependent Manner

View Article: PubMed Central - PubMed

ABSTRACT

Intensive care unit (ICU) patients are often overtly subjected to mechanical ventilation and immobilization, which leads to impaired limb and respiratory muscle function. The latter, termed ventilator-induced diaphragm dysfunction (VIDD) has recently been related to compromised heat shock protein (Hsp) activation. The administration of a pharmacological drug BGP-15 acting as a Hsp chaperone co-inducer has been found to partially alleviate VIDD in young rats. Considering that the mean age in the ICU is increasing, we aimed to explore whether the beneficial functional effects are also present in old rats. For that, we exposed young (7–8 months) and old (28–32 months) rats to 5-day controlled mechanical ventilation and immobilization with or without systemic BGP-15 administration. We then dissected diaphragm muscles, membrane–permeabilized bundles and evaluated the contractile function at single fiber level. Results confirmed that administration of BGP-15 restored the force-generating capacity of isolated muscle cells from young rats in conjunction with an increased expression of Hsp72. On the other hand, our results highlighted that old rats did not positively respond to the BGP-15 treatment. Therefore, it is of crucial importance to comprehend in more depth the effect of VIDD on diaphragm function and ascertain any further age-related differences.

No MeSH data available.


Related in: MedlinePlus

Individual rat single diaphragm muscle fiber cross sectional area (CSA) measured at fixed sarcomere length in control animals (individual rats: young n = 4 and old n = 2) compared with age-matched animals exposed to CMV for 5 days without (individual rats: young n = 3 and old n = 2) and with BGP-15 (individual rats: young n = 3 and old n = 3). Values are averages of individual data from the different animals and the red line indicates the average for each group. (Filled circles, young; open circles, old; red line, group average). Significance level, *p < 0.05.
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Figure 2: Individual rat single diaphragm muscle fiber cross sectional area (CSA) measured at fixed sarcomere length in control animals (individual rats: young n = 4 and old n = 2) compared with age-matched animals exposed to CMV for 5 days without (individual rats: young n = 3 and old n = 2) and with BGP-15 (individual rats: young n = 3 and old n = 3). Values are averages of individual data from the different animals and the red line indicates the average for each group. (Filled circles, young; open circles, old; red line, group average). Significance level, *p < 0.05.

Mentions: A total of 306 diaphragm muscle fibers met the acceptance criteria and were included in this study. Averages were based on an average of 13 fibers per animal. The fiber cross sectional area (CSA) from the old control animals was significantly larger (p < 0.05) than in young adult controls (Figure 2). Five days deep sedation, neuromuscular blockade (NMB) and CMV resulted in a compensatory hypertrophy (p < 0.05) in the young. In the old control animals, there is a trend toward an increased CSA, although not statistically significant (Figure 2). BGP-15 administration had no significant effect on muscle fiber size compared with untreated animals during 5 days CMV irrespective animal age (Figure 2). The IIx MyHC isoform was dominant in all groups and there were no statistically significant differences in MyHC isoform expression between groups in response to age, CMV or BGP-15 administration (Figure 3).


Targeting Heat Shock Proteins Mitigates Ventilator Induced Diaphragm Muscle Dysfunction in an Age-Dependent Manner
Individual rat single diaphragm muscle fiber cross sectional area (CSA) measured at fixed sarcomere length in control animals (individual rats: young n = 4 and old n = 2) compared with age-matched animals exposed to CMV for 5 days without (individual rats: young n = 3 and old n = 2) and with BGP-15 (individual rats: young n = 3 and old n = 3). Values are averages of individual data from the different animals and the red line indicates the average for each group. (Filled circles, young; open circles, old; red line, group average). Significance level, *p < 0.05.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5037190&req=5

Figure 2: Individual rat single diaphragm muscle fiber cross sectional area (CSA) measured at fixed sarcomere length in control animals (individual rats: young n = 4 and old n = 2) compared with age-matched animals exposed to CMV for 5 days without (individual rats: young n = 3 and old n = 2) and with BGP-15 (individual rats: young n = 3 and old n = 3). Values are averages of individual data from the different animals and the red line indicates the average for each group. (Filled circles, young; open circles, old; red line, group average). Significance level, *p < 0.05.
Mentions: A total of 306 diaphragm muscle fibers met the acceptance criteria and were included in this study. Averages were based on an average of 13 fibers per animal. The fiber cross sectional area (CSA) from the old control animals was significantly larger (p < 0.05) than in young adult controls (Figure 2). Five days deep sedation, neuromuscular blockade (NMB) and CMV resulted in a compensatory hypertrophy (p < 0.05) in the young. In the old control animals, there is a trend toward an increased CSA, although not statistically significant (Figure 2). BGP-15 administration had no significant effect on muscle fiber size compared with untreated animals during 5 days CMV irrespective animal age (Figure 2). The IIx MyHC isoform was dominant in all groups and there were no statistically significant differences in MyHC isoform expression between groups in response to age, CMV or BGP-15 administration (Figure 3).

View Article: PubMed Central - PubMed

ABSTRACT

Intensive care unit (ICU) patients are often overtly subjected to mechanical ventilation and immobilization, which leads to impaired limb and respiratory muscle function. The latter, termed ventilator-induced diaphragm dysfunction (VIDD) has recently been related to compromised heat shock protein (Hsp) activation. The administration of a pharmacological drug BGP-15 acting as a Hsp chaperone co-inducer has been found to partially alleviate VIDD in young rats. Considering that the mean age in the ICU is increasing, we aimed to explore whether the beneficial functional effects are also present in old rats. For that, we exposed young (7&ndash;8 months) and old (28&ndash;32 months) rats to 5-day controlled mechanical ventilation and immobilization with or without systemic BGP-15 administration. We then dissected diaphragm muscles, membrane&ndash;permeabilized bundles and evaluated the contractile function at single fiber level. Results confirmed that administration of BGP-15 restored the force-generating capacity of isolated muscle cells from young rats in conjunction with an increased expression of Hsp72. On the other hand, our results highlighted that old rats did not positively respond to the BGP-15 treatment. Therefore, it is of crucial importance to comprehend in more depth the effect of VIDD on diaphragm function and ascertain any further age-related differences.

No MeSH data available.


Related in: MedlinePlus