Targeting TFEB-mediated proteostatic maintenance in skeletal muscle dysfunction in HFpEF
Description: Heart failure with preserved ejection fraction (HFpEF) is a major challenge in cardiovascular medicine, accounting for over half of all heart failure cases and predominantly affecting older adults. Despite its high prevalence, effective treatments remain limited, as most therapeutic approaches fail to address the multi-organ nature of HFpEF. Growing evidence highlights skeletal muscle (SM) dysfunction as a key contributor to HFpEF pathophysiology. Aging-related muscle loss and dysfunction, known as sarcopenia, is more severe in HFpEF and is associated with reduced exercise capacity, higher hospitalization rates and increased mortality. However, the molecular mechanisms underlying SM dysfunction in HFpEF and its systemic effects remain poorly understood, particularly in aging populations. The maintenance of protein homeostasis, or proteostasis, is critical for muscle health. Dysregulated proteostasis has been implicated in aging, cardiac disease, and SM deterioration. My preliminary data suggest that transcription factor EB (TFEB), a key regulator of autophagy and mitochondrial protein turnover (synthesis and degradation), is suppressed in the SM of old mice with HFpEF. SM also function as a secretory organ, releasing signaling molecules (myokines) that influence other organs, including the heart. In HFpEF, disruptions in the secretion of key myokines may contribute to disease progression by impairing muscle-to-heart signaling pathways. My overall hypothesis is that TFEB-related proteostatic maintenance is disrupted in the SM of aged HFpEF mice, leading to exacerbated muscle dysfunction and dysregulated myokine secretion, and that enhancing muscle proteostasis through SM-specific TFEB overexpression will improve overall HFpEF outcomes. This study aims to: (I) investigate the proteostatic mechanisms underlying SM dysfunction in HFpEF, (II) identify HFpEF-related alterations in the muscle secretome, and (III) evaluate the potential of targeting TFEB-mediated muscle proteostasis to enhance muscle health and improve overall HFpEF outcomes. This research takes a novel approach by focusing on the muscle-to-heart connection in HFpEF, aiming to uncover how SM dysfunction contributes to the multi-organ syndrome of HFpEF. By exploring new therapeutic strategies targeting muscle proteostasis in HFpEF, this work may help develop more effective treatment options, particularly for older patients.
Funder: American Heart Association
Amount: $231,000
Funding type: fellowship
Funder scheme: Career Development Award
Start date: 2025-04-01
End date: 2028-03-31
Investigators: Kamil Kobak, Kamil Kobak
Institution: Oklahoma Medical Research Foundation
Subfield: Molecular Biology
Domain: Life Sciences
Funded outputs count: 2
Funder award ID: 25CDA1432894
OpenAlex ID: G2601368206