Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice

Abstract

<jats:p>Diastolic dysfunction is a prominent feature of cardiac aging in both mice and humans. We show here that 8-week treatment of old mice with the mitochondrial targeted peptide SS-31 (elamipretide) can substantially reverse this deficit. SS-31 normalized the increase in proton leak and reduced mitochondrial ROS in cardiomyocytes from old mice, accompanied by reduced protein oxidation and a shift towards a more reduced protein thiol redox state in old hearts. Improved diastolic function was concordant with increased phosphorylation of cMyBP-C Ser282 but was independent of titin isoform shift. Late-life viral expression of mitochondrial-targeted catalase (mCAT) produced similar functional benefits in old mice and SS-31 did not improve cardiac function of old mCAT mice, implicating normalizing mitochondrial oxidative stress as an overlapping mechanism. These results demonstrate that pre-existing cardiac aging phenotypes can be reversed by targeting mitochondrial dysfunction and implicate mitochondrial energetics and redox signaling as therapeutic targets for cardiac aging.</jats:p>

Pharmacological targeting of mitochondrial function and reactive oxygen species production prevents colon 26 cancer-induced cardiorespiratory muscle weakness

“…Further, we show that SS-31 treatment preserved mitochondrial function in both cardiac and diaphragm muscle from C26 mice by preserving oxidative phosphorylation and preventing proton leak into the mitochondrial matrix. A similar positive influence of SS-31 on cardiac and skeletal muscle in heart failure was recently shown which implicated mitochondrial bioenergetics and redox signaling in the development of muscle dysfunction [31,32]. This is important because increased proton leak can augment oxidant production within the mitochondrial matrix leading to a disruption of redox balance within the muscle tissue [33,34].…”

Reduction of elevated proton leak rejuvenates mitochondria in the aged cardiomyocyte

“…We suggest that the restoration of aged mitochondrial function that is conferred by SS-31 is directly attributable to this effect. However, the resulting enhancement in diastolic function is likely to require downstream changes, as the functional benefit took up to 8 weeks to reach full effect, and required post-translational modifications of contractile protein elements ( Chiao et al, 2020 ). It is increasingly recognized that mitochondrial function, including redox status and energetics, has far-reaching effects, including epigenetic alterations and post-translational modifications ( Olgar et al, 2019 ).…”

“…In aged mice, SS-31 ameliorates kidney glomerulopathy ( Sweetwyne et al, 2017 ) and brain oxidative stress ( Hao et al, 2017 ) and has shown beneficial effects on skeletal muscle performance ( Siegel et al, 2013 ). We have recently shown that administration of SS-31 to 24-month-old mice for 8 weeks reverses the age-related decline in diastolic function, increasing the E/A from just above 1.0 to 1.22, restoring this parameter 35% toward that of young (5-month-old) mice ( Chiao et al, 2020 ). However, how SS-31 benefits and protects aged cardiac cells remains unclear.…”

Protein thiol oxidation in the rat lung following e-cigarette exposure

“…For quantitative analysis, MASIC was used to extract the reporter ion intensities from the raw data [ 19 ]. An in-house R script was used to link the peptide identifications and quantifications as described before [ 20 ]. Reporter ion intensities for PSMs corresponding to the same unique peptide were summed and log2 transformed.…”