Akinborewa, O.; Prabakaran, A. D.; Durumutla, H. B.; Latimer, H.; McFarland, K.; Quattrocelli, M.

Striated muscles, including cardiac and skeletal muscle, share key structural features but are governed by distinct regulatory mechanisms that maintain their function and integrity. Here, we identify the previously uncharacterized Lrrc14b gene as a striated muscle-specific gene with enriched expression in cardiac and skeletal myocytes. Germline Lrrc14b deletion in mice led to progressive left ventricular dilation and systolic dysfunction in both sexes, consistent with features of heart failure with reduced ejection fraction. Notably, AAV-mediated re-expression of Lrrc14b in knockout mice restored cardiac function. In contrast, Lrrc14b deletion in skeletal muscle resulted in increased muscle mass, myofiber cross-sectional area and hindlimb force, whereas skeletal-muscle-specific overexpression induced muscle atrophy and functional decline independent from aging. These findings establish LRRC14B as a tissue-specific regulator of striated muscle function and underscore its potential relevance in cardiovascular and musculoskeletal diseases.