Late-in-life treadmill-training rejuvenates autophagy, protein aggregate clearance, and function in mouse hearts

Abstract

There is evidence for a progressive decline of protein quality control mechanisms during the process of cardiac aging. This enables the accumulation of protein aggregates and damaged organelles that contribute to age-associated cardiac dysfunction. Macroautophagy (referred to as autophagy) is the process by which post-mitotic cells such as cardiomyocytes clear defective proteins and organelles. We hypothesized that late-in-life exercise training improves autophagy, protein aggregate clearance, and function that is otherwise dysregulated in hearts from old vs adult mice. As expected, 24-month old male C57BL/6J mice (old) exhibited : (i) repressed autophagosome formation and protein aggregate accumulation in the heart; (ii) systolic and diastolic dysfunction; and (iii) reduced exercise capacity, vs. 8-month old (adult) mice (all p< .05). Separate cohorts of 21 month old mice completed a 3-month progressive resistance treadmill-running program (old-ETR) that improved (all < .05) : (i) body composition; (ii) exercise capacity; and (iii) soleus muscle citrate synthase activity, vs. age-matched mice that did not train (old-SED). Importantly, (iv) protein expression of autophagy markers indicated trafficking of the autophagosome to the lysosome increased, (v) protein aggregate clearance improved, and (vi) overall function was enhanced (all p<0.05), in hearts from old-ETR vs. old-SED mice. Dietary maneuvers and pharmacological interventions shown to elevate basal autophagy are reported to mitigate / reverse age-associated cardiac dysfunction. Here we show the first evidence that a physiological intervention initiated late-in-life improves autophagic flux, protein aggregate clearance, and overall function in mouse hearts.

Exercise‐mediated autophagy in cardiovascular diseases

“…Furthermore, in the study of No et al, 37 eight-weeks of treadmill exercise in aging rats resulted in reduced Pink, Parkin, and LC3 II protein expression, and increased mitochondrial oxygen respiration, hydrogen peroxide emission, and calcium (Ca 2+ ) retention capacity in the myocardium, which indicated that long-term exercise also reduced aging induced mitochondrial dysfunctions and excessive autophagy in the heart. Similar conclusions were also found in the study of Cho et al 38 : long-term treadmill training intervention mitigated excessive autophagic flux and improved protein aggregate clearance as well as damaged contractile performance in mouse hearts.…”