Functional properties of skeletal muscle from transgenic animals with upregulated heat shock protein 70

Nosek, Thomas M.; Brotto, Marco; Essig, David A.; Mestril, Ruben; Conover, Richard C.; Dillmann, Wolfgang H.; Kolbeck, Ralph C.

doi:10.1152/physiolgenomics.2000.4.1.25

Cited by 25 publications

(20 citation statements)

References 26 publications

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“…It has also been reported that DOX-generated ROS induce apoptosis by activating p38 MAPKs subunits ␣ and ␤. Interestingly, heat shock proteins (HSPs), which are induced in response to stress, have been found to be phosphorylated by the MAPK-assisted protein kinase 2 (MAPKAP-2, downstream of p38 MAPK), and the phosphorylated HSPs can act as negative regulators of apoptosis (5, 6), suggesting that induction of HSPs should regulate the p38 MAPK and, possibly, inhibit DOX-induced apoptosis, although this novel hypothesis remains untested.Cardioprotection by small HSPs against ischemia-reperfusion injury and other oxidative stresses has been investigated recently (23,33,37,40). Specifically, HSP27 and its murine homolog HSP25 have been shown to play important roles in…”

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confidence: 99%

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Heat shock protects cardiac cells from doxorubicin-induced toxicity by activating p38 MAPK and phosphorylation of small heat shock protein 27

Venkatakrishnan¹,

Tewari²,

Moldovan³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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. Heat shock protects cardiac cells from doxorubicin-induced toxicity by activating p38 MAPK and phosphorylation of small heat shock protein 27. Am J Physiol Heart Circ Physiol 291: H2680 -H2691, 2006. First published June 16, 2006 doi:10.1152/ajpheart.00395.2006 and its derivatives are used as chemotherapeutic drugs to treat cancer patients. However, production of DOX-mediated reactive oxygen species (ROS) by prolonged use of these drugs has been found to cause dilative cardiomyopathy and congestive heart failure. Thus various preventive modalities have been developed to avoid this side effect. We have found that the DOX-mediated oxidant-induced toxicity in cardiac cells could be minimized by hyperthermia-induced small heat shock protein 27 (HSP27); that is, this protein acts as an endogenous antioxidant against DOX-derived oxidants such as H 2O2. Heat shockinduced HSP27 was found to act as an antiapoptotic protein (reducing ROS and Bax-to-Bcl2 ratio) against DOX, and its phosphorylated isoforms stabilized F-actin remodeling in DOX-treated cardiac cells and, hence, attenuated the toxicity. Protein kinase assays and proteomic analyses suggested that higher expression of HSP27 and its phosphorylation are responsible for the protection in heat-shocked cells. Two-dimensional gel electrophoresis showed six isoforms (nonphosphorylated and phosphorylated) of HSP27. Matrix-assisted laser desorption/ionization time of flight analyses showed ␣-and ␤-isoforms of HSP27, which are phosphorylated by various protein kinases. Ser 15 and Ser 85 phosphorylation of HSP27 by MAPK-assisted protein kinase 2 was found to be the key mechanism in reduction of apoptosis and facilitation of F-actin remodeling. The present study illustrates that hyperthermia protects cells from DOX-induced death through induction and phosphorylation of HSP27 and its antiapoptotic and actin-remodeling activities. apoptosis; cardiomyopathy; hyperthermia ADRIAMYCIN DERIVATIVES, such as doxorubicin (DOX), are widely used as anticancer drugs. Unfortunately, prolonged use of these drugs to treat cancer patients has resulted in the development of dilative cardiomyopathy (DCM) and congestive heart failure (CHF) within a few years after cessation of treatment, irrespective of age and race (36). To avoid this side effect, new anthracyclin derivatives with less toxicity to the heart, new formulations in the form of encapsulation into delivery vehicles such as microemulsions, and new targeted delivery modalities to selectively deliver the drug to the desired site (preventing accumulation in the heart) have emerged (39).However, there has been no significant improvement in our ability to avoid this problem, and this effect has not been completely eliminated. At the same time, attempts to understand the actual mechanism of DOX-induced DCM and CHF have been appearing with increasing frequency in recent literature. Fortunately, the mechanisms whereby DOX and its analogs kill tumor cells (intended effect) and cause DCM and CHF (unwanted effects) are different, indicating...

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confidence: 99%

“…Cardioprotection by small HSPs against ischemia-reperfusion injury and other oxidative stresses has been investigated recently (23,33,37,40). Specifically, HSP27 and its murine homolog HSP25 have been shown to play important roles in…”

mentioning

confidence: 99%

Heat shock protects cardiac cells from doxorubicin-induced toxicity by activating p38 MAPK and phosphorylation of small heat shock protein 27

Venkatakrishnan¹,

Tewari²,

Moldovan³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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“…It has been observed that overexpression of HSP72 suppresses expression of HSC70 (18,24). Thus one possible explanation of the findings is that the overexpressed HSP72 inhibits the expression of HSC70 and then replaces it in key functions in the normal, noninjured cell.…”

Section: Discussionmentioning

confidence: 99%

Effect of mutation of amino acids 246–251 (KRKHKK) in HSP72 on protein synthesis and recovery from hypoxic injury

Voss¹,

Gupta²,

Stice³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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Heat shock protein (HSP)72, the inducible form of HSP70, protects cells against a variety of injuries, but underlying mechanisms are poorly defined. To investigate the protective effects of HSP72, multiple clones expressing wild-type (WT) HSP72 and two mutants with defective nucleolar and nuclear localization (M45 and 985A, respectively) were made with the tet-off system in C2C12 cells. Four different parameters of cell function/injury were examined after simulated ischemia: protein synthesis, polysome formation, DNA synthesis, and lactate dehydrogenase (LDH release). Overexpression of WT HSP72 was also compared to nontransfected C2C12 cells. As expected, overexpression of HSP72 protected against simulated ischemia and reoxygenation for all parameters. In contrast, both M45 and 985A showed abnormal protein synthesis and polysome formation, both after simulated ischemia and under control conditions. Total RNA was slightly reduced in M45 and 985A at baseline, but 1 h after hypoxia, RNA levels were protected in all clones but significantly decreased in nontransfected C2C12 cells. Clones expressing 985A had nuclear retention of mRNA, suggesting that HSP72 is needed for nuclear export of RNA. All clones, both WT and mutant, had protection of DNA synthesis compared to C2C12 cells, but 985A had greater release of LDH after injury than any other group. These results support a multifactoral protective effect of HSP72, some aspects dependent on nuclear localization with stress and some not. The protection of protein synthesis and polysome formation, and abnormalities in these with the mutants, support a role for HSP72 in these processes both in the normal cell and in injury.

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“…Other studies have also showed no protection to contracting skeletal muscles (Nosek et al 2000). However, more recent studies suggest that HSPs may be beneficial to skeletal muscle under certain conditions of stress (McArdle et al 2004;Kayani et al 2008;Touchberry et al 2012;Liu et al 2013).…”

Section: Introductionmentioning

confidence: 97%

The effect of heat stress on skeletal muscle contractile properties

Locke

Celotti

2014

Cell Stress and Chaperones

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An elevated heat-shock protein (HSP) content protects cells and tissues, including skeletal muscles, from certain stressors. We determined if heat stress and the elevated HSP content that results is correlated with protection of contractile characteristics of isolated fast and slow skeletal muscles when contracting at elevated temperatures. To elevate muscle HSP content, one hindlimb of Sprague-Dawley rats (21-28 days old, 70-90 g) was subjected to a 15 min 42°C heat-stress. Twenty-four hours later, both extensor digitorum longus (EDL) and soleus muscles were removed, mounted in either 20°C or 42°C Krebs-Ringer solution, and electrically stimulated. Controls consisted of the same muscles from the contra-lateral (non-stressed) hindlimbs as well as muscles from other (unstressed) animals. Isolated muscles were twitched and brought to tetanus every 5 min for 30 min. As expected, HSP content was elevated in muscles from the heatstressed limbs when compared with controls. Regardless of prior treatment, both EDL and soleus twitch tensions were lower at 42°C when compared with 20°C. In addition, when incubated at 42°C, both muscles showed a drop in twitch tension between 5 and 30 min. For tetanic tension, both muscles also showed an increase in tension between 5 and 30 min when stimulated at 20°C regardless of treatment but when stimulated at 42°C no change was observed. No protective effect of an elevated HSP content was observed for either muscle. In conclusion, although heat stress caused an elevation in HSP content, no protective effects were conferred to isolated contracting muscles.

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Functional properties of skeletal muscle from transgenic animals with upregulated heat shock protein 70

Cited by 25 publications

References 26 publications

Heat shock protects cardiac cells from doxorubicin-induced toxicity by activating p38 MAPK and phosphorylation of small heat shock protein 27

Heat shock protects cardiac cells from doxorubicin-induced toxicity by activating p38 MAPK and phosphorylation of small heat shock protein 27

Effect of mutation of amino acids 246–251 (KRKHKK) in HSP72 on protein synthesis and recovery from hypoxic injury

The effect of heat stress on skeletal muscle contractile properties

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