Tags

Type your tag names separated by a space and hit enter

SS31, a Mitochondrially Targeted Antioxidant, Prevents Sepsis Induced Reductions in Diaphragm Strength and Endurance.

Abstract

Sepsis-induced diaphragm dysfunction contributes to respiratory failure and mortality in critical illness. There are no treatments for this form of diaphragm weakness. Studies show that sepsis-induced muscle dysfunction is triggered by enhanced mitochondrial free radical generation. We tested the hypothesis that SS31, a mitochondrially-targeted antioxidant, would attenuate sepsis-induced diaphragm dysfunction. Four groups of mice were studied: (a) sham operated controls, (b) sham operated+SS31 (10 mg/kg/day), (c) cecal ligation puncture (CLP), and (d) CLP+SS31. Forty-eight hours post-operatively, diaphragm strips with attached phrenic nerves were isolated and the following assessed: muscle field stimulated force-frequency curves, nerve stimulated force-frequency curves, and muscle fatigue. We also measured calpain activity, 20S proteasomal activity, myosin heavy chain (MHC) levels, mitochondrial function and aconitase activity, an index of mitochondrial superoxide generation. Sepsis markedly reduced diaphragm force generation; SS31 prevented these decrements. Diaphragm specific force generation averaged 30.2±1.4, 9.4±1.8, 25.5±2.3, and 27.9±0.6 N/cm2 for sham, CLP, sham+SS31, and CLP+SS31 groups (p<0.001). Similarly, with phrenic nerve stimulation, CLP depressed diaphragm force generation, effects prevented by SS31. During endurance trials, force was significantly reduced with CLP and SS31 prevented these reductions (p<0.001). Sepsis also increased diaphragm calpain activity, increased 20S proteasomal activity, decreased MHC levels, reduced mitochondrial function (state 3 rates and ATP generation), and reduced aconitase activity; SS31 prevented each of these sepsis-induced alterations (p≤0.017 for all indices). SS31 prevents sepsis-induced diaphragm dysfunction, preserving force generation, endurance and mitochondrial function. Compounds with similar mechanisms of action may be useful therapeutically to preserve diaphragm function in septic, critically ill patients.

Authors+Show Affiliations

Department of Internal Medicine, University of Kentucky, United States.Department of Internal Medicine, University of Kentucky, United States.Department of Physiology, University of Kentucky, United States.Department of Internal Medicine, University of Kentucky, United States.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31944887

Citation

Supinski, Gerald S., et al. "SS31, a Mitochondrially Targeted Antioxidant, Prevents Sepsis Induced Reductions in Diaphragm Strength and Endurance." Journal of Applied Physiology (Bethesda, Md. : 1985), 2020.
Supinski GS, Wang L, Schroder EA, et al. SS31, a Mitochondrially Targeted Antioxidant, Prevents Sepsis Induced Reductions in Diaphragm Strength and Endurance. J Appl Physiol. 2020.
Supinski, G. S., Wang, L., Schroder, E. A., & Callahan, L. A. P. (2020). SS31, a Mitochondrially Targeted Antioxidant, Prevents Sepsis Induced Reductions in Diaphragm Strength and Endurance. Journal of Applied Physiology (Bethesda, Md. : 1985), doi:10.1152/japplphysiol.00240.2019.
Supinski GS, et al. SS31, a Mitochondrially Targeted Antioxidant, Prevents Sepsis Induced Reductions in Diaphragm Strength and Endurance. J Appl Physiol. 2020 Jan 16; PubMed PMID: 31944887.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - SS31, a Mitochondrially Targeted Antioxidant, Prevents Sepsis Induced Reductions in Diaphragm Strength and Endurance. AU - Supinski,Gerald S, AU - Wang,Lin, AU - Schroder,Elizabeth A, AU - Callahan,Leigh Ann P, Y1 - 2020/01/16/ PY - 2020/1/17/entrez PY - 2020/1/17/pubmed PY - 2020/1/17/medline KW - Diaphragm force generation KW - SS31 KW - diaphragm fatigue KW - neuromuscular transmission KW - sepsis JF - Journal of applied physiology (Bethesda, Md. : 1985) JO - J. Appl. Physiol. N2 - Sepsis-induced diaphragm dysfunction contributes to respiratory failure and mortality in critical illness. There are no treatments for this form of diaphragm weakness. Studies show that sepsis-induced muscle dysfunction is triggered by enhanced mitochondrial free radical generation. We tested the hypothesis that SS31, a mitochondrially-targeted antioxidant, would attenuate sepsis-induced diaphragm dysfunction. Four groups of mice were studied: (a) sham operated controls, (b) sham operated+SS31 (10 mg/kg/day), (c) cecal ligation puncture (CLP), and (d) CLP+SS31. Forty-eight hours post-operatively, diaphragm strips with attached phrenic nerves were isolated and the following assessed: muscle field stimulated force-frequency curves, nerve stimulated force-frequency curves, and muscle fatigue. We also measured calpain activity, 20S proteasomal activity, myosin heavy chain (MHC) levels, mitochondrial function and aconitase activity, an index of mitochondrial superoxide generation. Sepsis markedly reduced diaphragm force generation; SS31 prevented these decrements. Diaphragm specific force generation averaged 30.2±1.4, 9.4±1.8, 25.5±2.3, and 27.9±0.6 N/cm2 for sham, CLP, sham+SS31, and CLP+SS31 groups (p<0.001). Similarly, with phrenic nerve stimulation, CLP depressed diaphragm force generation, effects prevented by SS31. During endurance trials, force was significantly reduced with CLP and SS31 prevented these reductions (p<0.001). Sepsis also increased diaphragm calpain activity, increased 20S proteasomal activity, decreased MHC levels, reduced mitochondrial function (state 3 rates and ATP generation), and reduced aconitase activity; SS31 prevented each of these sepsis-induced alterations (p≤0.017 for all indices). SS31 prevents sepsis-induced diaphragm dysfunction, preserving force generation, endurance and mitochondrial function. Compounds with similar mechanisms of action may be useful therapeutically to preserve diaphragm function in septic, critically ill patients. SN - 1522-1601 UR - https://www.unboundmedicine.com/medline/citation/31944887/SS31,_a_Mitochondrially_Targeted_Antioxidant,_Prevents_Sepsis_Induced_Reductions_in_Diaphragm_Strength_and_Endurance L2 - http://journals.physiology.org/doi/full/10.1152/japplphysiol.00240.2019?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -