Abstract 298: Age-Related Cardiac Muscle Sarcopenia in Mice
Background: Age-related sarcopenia has been well-characterized in skeletal muscle and aortic smooth muscle cells. Whether cardiac sarcopenia occurs with aging, however, has not been described. We studied the cardiac sarcopenia and related structural and functional changes in mice. Mice do not develop hypertension with age, even into senescence, which allowed us to decouple vascular effects and monitor cardiac-dependent variables over time.
Methods: We evaluated adult (7.5±0.5 months; n=27) and senescent (31.8±0.4 months; n=26) C57/BL6 mice for indications of cardiac sarcopenia using echocardiography, histological, and biochemical assessments. Then, we established a mathematical model to describe the relationship between age-related changes in myocardial structure and function.
Results: Compared to adult mice, senescent mice showed increased end diastolic dimension (3.79±0.07 mm to 4.15±0.08 mm; p<0.05), decreased wall thickness (0.80±0.02 mm to 0.72±0.02 mm; p<0.05), and decreased ejection fraction (69±1% to 60±2%; p<0.05), indicating dilation and reduced contractile performance. Interstitial fibrosis was punctate but doubled in the senescent mice, indicative of reparative fibrosis. By electrocardiogram analysis, PR interval and QRS interval increased and R amplitude decreased in the senescent mice, indicating prolonged conduction times consistent with increased fibrosis. Myocyte cell numbers, measured as a percentage of nuclei, decreased 22% in the senescent group (p<0.05). Intracellular lipid accumulation was accompanied by a concomitant decrease in glycogen stores in the senescent mice. Mathematical modeling illustrated an inter-relationship among ventricular dimensions, fibrosis, and mechanical stress in a defined manner. This relationship constructed a feedback loop between mechanical properties and ventricular dimension, and led to changes in LV function.
Conclusion: This is the first report to document age-related cardiac muscle sarcopenia in mice and to provide a mathematical model of the aging process. Our model demonstrates that the decrease in cell numbers, the increase in reparative fibrosis, and the increase in mechanical stress interact together and ultimately depress the left ventricular function.