Cardiac Myosin Binding Protein-C phosphorylation is essential to preserve diastolic function in aging hearts
Description: Incidence and prevalence of heart failure (HF) increase with age. HF with preserved ejection fraction (HFpEF) is defined as heart failure with EF more than 50% and currently does not have an effective treatment. HFpEF is the most common type of HF in the elderly. Impaired relaxation, also known as diastolic dysfunction is believed to be the dominant cause of HFpEF. Cardiac myosin binding protein-C (cMyBP-C), which is a heart muscle thick filament protein, can regulate cross-bridge attach/detachment processes by its phosphorylation status. Thus, we hypothesize that phosphorylated cMyBP-C enhances cardiac relaxation even with aging. To test our hypothesis, we will age mouse models of wild-type equivalent cMyBP-C(tWT), phosphorylation deficient cMyBP-C(t3SA), and phosphorylation mimetic cMyBP-C(t3SD) to 18 months to mimic a human age of 60-70 years. We will use serial echocardiography to follow development of diastolic dysfunction. We will use pressure-volume measurements to confirm systolic and diastolic functions at 18 months of age. AAV9 carrying phosphorylation mimetic cMyBP-C with S273D/S282D/S302D mutations will be injected to cMyBP-C(tWT) mice to rescue aging related deterioration of diastolic function. We will isolate intact papillary muscles from aged hearts and measure force and intracellular calcium concentration [Ca2+]i to differentiate contributions of [Ca2+]i handling versus cross-bridge detachment, thereby, elucidating the underlying mechanism of phosphorylated cMyBP-C enhancing relaxation. We will also study other potential contributors to age-related diastolic dysfunction such as fibrosis, elevated blood pressure, and hyperglycemia. Additionally, we will examine post-translational modifications of cMyBP-C that may occur with aging, as well as other factors that may affect diastolic function such as compensatory phosphorylation of other contractile proteins and differences in the expression of calcium handling proteins. We expect that: (1) hypo-phosphorylated cMyBP-C(t3SA) will develop diastolic dysfunction early in life, (2) normally phosphorylatable cMyBP-C(tWT) will develop diastolic dysfunction with aging, and (3) phosphorylation mimetic cMyBP-C(t3SD) will maintain a normal diastolic function even with aging. Results can lead to new treatments to prevent or reverse age-related development of diastolic dysfunction.
Funder: American Heart Association
Amount: $106,400
Funding type: fellowship
Funder scheme: Postdoctoral Fellowship
Start date: 2016-07-01
End date: 2018-06-30
Investigators: Paola Rosas, Paola Rosas
Institution: Texas A&M University Health Science Center
Funded outputs count: 1
Funder award ID: 16POST29990013
OpenAlex ID: G2739344841