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

• Published in: Aging cell Vol. 20; no. 10; pp. e13467 - n/a
• Main Authors: Cho, Jae Min, Park, Seul‐Ki, Ghosh, Rajeshwary, Ly, Kellsey, Ramous, Caroline, Thompson, Lauren, Hansen, Michele, Mattera, Maria Sara de Lima Coutinho, Pires, Karla Maria, Ferhat, Maroua, Mookherjee, Sohom, Whitehead, Kevin J., Carter, Kandis, Buffolo, Márcio, Boudina, Sihem, Symons, J. David
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.10.2021; John Wiley and Sons Inc
• Subjects: Adolescent; Adult; Age; Aged; Aged, 80 and over; Aging; Animals; Autophagy; Autophagy - physiology; Body composition; Cardiac function; Cardiomyocytes; Cardiomyopathy; Citrate synthase; Exercise; Fitness equipment; Fitness training programs; Heart - physiopathology; Heart diseases; Humans; Hypotheses; Male; Mice; Middle Aged; Muscle contraction; Organelles; Original Paper; Original Papers; Oxidative stress; Phagocytosis; Physical Conditioning, Animal - methods; Physical fitness; Physical training; protein aggregates; Protein Aggregates - physiology; Protein expression; Proteins; Quality control; Running; Soleus muscle; Young Adult; exercise; cardiac function; protein aggregates; aging
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/acel.13467

Protein quality control mechanisms decline during the process of cardiac aging. This enables the accumulation of protein aggregates and damaged organelles that contribute to age‐associated cardiac dysfunction. Macroautophagy 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 repressed autophagosome formation and protein aggregate accumulation in the heart, systolic and diastolic dysfunction, and reduced exercise capacity vs. 8‐month‐old (adult) mice (all p < 0.05). To investigate the influence of late‐in‐life exercise training, additional cohorts of 21‐month‐old mice did (old‐ETR) or did not (old‐SED) complete a 3‐month progressive resistance treadmill running program. Body composition, exercise capacity, and soleus muscle citrate synthase activity improved in old‐ETR vs. old‐SED mice at 24 months (all p < 0.05). Importantly, protein expression of autophagy markers indicate trafficking of the autophagosome to the lysosome increased, protein aggregate clearance improved, and overall function was enhanced (all p < 0.05) in hearts from old‐ETR vs. old‐SED mice. These data provide the first evidence that a physiological intervention initiated late‐in‐life improves autophagic flux, protein aggregate clearance, and contractile performance in mouse hearts. Aged sedentary mice exhibit reduced cardiac: steady‐state autophagy; autophagic flux; protein clearance; redox balance; mitochondria quality; and function. If aged mice initiate exercise training at the proper intensity, frequency, and duration, each of these age‐associated cardiac disruptions is mitigated.