Effects of exercise preconditioning and HSP72 on diaphragm muscle function during mechanical ventilation

Abstract

Background Mechanical ventilation (MV) is a life‐saving measure for patients in respiratory failure. However, prolonged MV results in significant diaphragm atrophy and contractile dysfunction, a condition referred to as ventilator‐induced diaphragm dysfunction (VIDD). While there are currently no clinically approved countermeasures to prevent VIDD, increased expression of heat shock protein 72 (HSP72) has been demonstrated to attenuate inactivity‐induced muscle wasting. HSP72 elicits cytoprotection via inhibition of NF‐κB and FoxO transcriptional activity, which contribute to VIDD. In addition, exercise‐induced prevention of VIDD is characterized by an increase in the concentration of HSP72 in the diaphragm. Therefore, we tested the hypothesis that increased HSP72 expression is required for the exercise‐induced prevention of VIDD. We also determined whether increasing the abundance of HSP72 in the diaphragm, independent of exercise, is sufficient to prevent VIDD. Methods Cause and effect was determined by inhibiting the endurance exercise‐induced increase in HSP72 in the diaphragm of exercise trained animals exposed to prolonged MV via administration of an antisense oligonucleotide targeting HSP72. Additional experiments were performed to determine if increasing HSP72 in the diaphragm via genetic (rAAV‐HSP72) or pharmacological (BGP‐15) overexpression is sufficient to prevent VIDD. Results Our results demonstrate that the exercise‐induced increase in HSP72 protein abundance is required for the protective effects of exercise against VIDD. Moreover, both rAAV‐HSP72 and BGP‐15‐induced overexpression of HSP72 were sufficient to prevent VIDD. In addition, modification of HSP72 in the diaphragm is inversely related to the expression of NF‐κB and FoxO target genes. Conclusions HSP72 overexpression in the diaphragm is an effective intervention to prevent MV‐induced oxidative stress and the transcriptional activity of NF‐κB and FoxO. Therefore, overexpression of HSP72 in the diaphragm is a potential therapeutic target to protect against VIDD.

Effects of aerobic and inspiratory training on skeletal muscle microRNA‐1 and downstream‐associated pathways in patients with heart failure

“…showed that exercise increases the expression of heat shock protein 72 (HSP72), which reduces the expression of atrophic transcript factors and oxidative stress. These responses preserve diaphragm muscle function in animals with diaphragm dysfunction . Molecular adaptations in respiratory muscles were out of the scope of our study.…”

The tortuous path of lactate shuttle discovery: From cinders and boards to the lab and ICU

“…It is risky to limit the examples of how ACSM colleagues have advanced science and medicine, since other important contributions are easily and unintentionally omitted. Nevertheless, contributions of the following individuals to physiology, and sports medicine should not be overlooked: Jere Mitchell, in cardiovascular physiology and medicine; 186 John Holloszy, in mitochondrial biogenesis; 187 L. Bruce Gladden, in the regulation of intermediary metabolism; 18 , 188 Jim Barnard, V. Reggie Edgerton, and Ken Baldwin, in muscle fiber heterogeneity; 47 , 48 Scott Powers, in redox signaling and preconditioning of the heart to cardiovascular insults; 189 Karl Wasserman and Jerry Dempsey, in pulmonary physiology and medicine; 25 , 190 Tom Fahey, in translating the lessons of physiology and sports medicine to the literature for health care professionals and the lay public; 191 , 192 , 193 and Tim White, in the administration of higher education ( https://www2.calstate.edu/csu-system/chancellor/Pages/meet-the-chancellor.aspx ). In the aggregate, our scientists, clinicians, and staff at the ACSM know well how the body works under stress, in illness, and after injury.…”

Cancer Takes a Toll on Skeletal Muscle by Releasing Heat Shock Proteins—An Emerging Mechanism of Cancer-Induced Cachexia

“…Thus, Hsp70/90 are considered mainly intracellular molecular chaperones, which makes them cytoprotective against stressful stimuli. In skeletal muscle cells, overexpression of Hsp70 protects against muscle damage and age-related muscle dysfunction [111] as well as disuse or mechanical ventilation-induced muscle atrophy [112,113,114]. However, under pathological conditions, Hsp70 and Hsp90 can be released into extracellular space where they act as DAMPs [115].…”