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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.


(A) MuRF1 gene expression (B) Atrogin-1 mRNA expression, according to real time PCR in the Diaphragm. 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 means of starting quantities + SEM. (Black, young; white, old. Significance level, **p < 0.01, ***p < 0.001.
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Figure 6: (A) MuRF1 gene expression (B) Atrogin-1 mRNA expression, according to real time PCR in the Diaphragm. 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 means of starting quantities + SEM. (Black, young; white, old. Significance level, **p < 0.01, ***p < 0.001.

Mentions: The most striking observation that we made was an increased expression of MuRF1 in only the young in response to 5 days CMV+BGP-15 compared to control values and to 5 days CMV alone (Figure 6A). Furthermore, we show that the transcriptional regulation of MuRF1 and atrogin-1 showed an initial trend of an upregulation after 5 days CMV in the young, however in the old the expression of both atrogene's appeared to be unaltered by 5 days CMV or by BGP-15 (Figures 6A,B). In both instances neither was seen to be statistically different in comparison to control values.


Targeting Heat Shock Proteins Mitigates Ventilator Induced Diaphragm Muscle Dysfunction in an Age-Dependent Manner
(A) MuRF1 gene expression (B) Atrogin-1 mRNA expression, according to real time PCR in the Diaphragm. 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 means of starting quantities + SEM. (Black, young; white, old. Significance level, **p < 0.01, ***p < 0.001.
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Figure 6: (A) MuRF1 gene expression (B) Atrogin-1 mRNA expression, according to real time PCR in the Diaphragm. 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 means of starting quantities + SEM. (Black, young; white, old. Significance level, **p < 0.01, ***p < 0.001.
Mentions: The most striking observation that we made was an increased expression of MuRF1 in only the young in response to 5 days CMV+BGP-15 compared to control values and to 5 days CMV alone (Figure 6A). Furthermore, we show that the transcriptional regulation of MuRF1 and atrogin-1 showed an initial trend of an upregulation after 5 days CMV in the young, however in the old the expression of both atrogene's appeared to be unaltered by 5 days CMV or by BGP-15 (Figures 6A,B). In both instances neither was seen to be statistically different in comparison to control values.

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.