Disruption of valosin-containing protein activity causes cardiomyopathy and reveals pleiotropic functions in cardiac homeostasis.

Valosin-containing protein (VCP), also known as p97, is an ATPase with diverse cellular functions, although the most highly characterized is targeting of misfolded or aggregated proteins to degradation pathways, including the endoplasmic reticulum-associated degradation (ERAD) pathway. However, how VCP functions in the heart has not been carefully examined despite the fact that human mutations in VCP cause Paget disease of bone and frontotemporal dementia, an autosomal dominant multisystem proteinopathy that includes disease in the heart, skeletal muscle, brain, and bone. Here we generated heart-specific transgenic mice overexpressing WT VCP or a VCPK524A mutant with deficient ATPase activity. Transgenic mice overexpressing WT VCP exhibit normal cardiac structure and function, whereas mutant VCP-overexpressing mice develop cardiomyopathy. Mechanistically, mutant VCP-overexpressing hearts up-regulate ERAD complex components and have elevated levels of ubiquitinated proteins prior to manifestation of cardiomyopathy, suggesting dysregulation of ERAD and inefficient clearance of proteins targeted for proteasomal degradation. The hearts of mutant VCP transgenic mice also exhibit profound defects in cardiomyocyte nuclear morphology with increased nuclear envelope proteins and nuclear lamins. Proteomics revealed overwhelming interactions of endogenous VCP with ribosomal, ribosome-associated, and RNA-binding proteins in the heart, and impairment of cardiac VCP activity resulted in aggregation of large ribosomal subunit proteins. These data identify multifactorial functions and diverse mechanisms whereby VCP regulates cardiomyocyte protein and RNA quality control that are critical for cardiac homeostasis, suggesting how human VCP mutations negatively affect the heart.

PROMIS Global Physical Health Subscale Strongly Correlates and Performs Similarly to the QuickDASH in Hand and Upper Extremity Patients.

BACKGROUND: The Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) is a validated, static hand and upper extremity patient-reported outcome measure (PROM) commonly used. However, with the growth of PROM implementation across orthopedic and plastic surgery clinics, it is beneficial to determine whether a more general PROM can be used to capture the same insights. This would ease implementation broadly. There is a paucity of literature assessing whether the QuickDASH and Patient-Reported Outcomes Measurement Information System (PROMIS) Global-10 are correlated and perform similarly. METHODS: Between June 2016 and December 2020, hand and upper extremity patients seeking care at clinics associated with a single quaternary academic medical center were identified. Those who completed the PROMIS Global-10 and QuickDASH as part of routine care were identified. The PROMIS Global-10 is divided into the PROMIS Global Physical Health and PROMIS Global Mental Health subscores. Spearman rho (ρ) correlations were calculated across PROMs, and ceiling and floor effects were determined. RESULTS: Across the 18 744 included patients, there was a strong correlation and strong-moderate correlation found between the QuickDASH and PROMIS Global Physical Health (ρ = 0.70, P < .001) and PROMIS Global Mental Health (ρ = 0.69, P < .001), respectively. Although small, QuickDASH demonstrates the worst floor effect (2.6%, [n = 478]), whereas PROMIS Global Mental Health demonstrated a much more notable ceiling effect (11%, [n = 2034]). CONCLUSIONS: The PROMIS Global-10 can be used to assess the functional status of patients presenting for hand and upper extremity concerns, while also capturing aspects of mental health. The PROMIS Global-10 may ease PROM implementation broadly.

Defective Flux of Thrombospondin-4 through the Secretory Pathway Impairs Cardiomyocyte Membrane Stability and Causes Cardiomyopathy.

Thrombospondins are stress-inducible secreted glycoproteins with critical functions in tissue injury and healing. Thrombospondin-4 (Thbs4) is protective in cardiac and skeletal muscle, where it activates an adaptive endoplasmic reticulum (ER) stress response, induces expansion of the ER, and enhances sarcolemmal stability. However, it is unclear if Thbs4 has these protective functions from within the cell, from the extracellular matrix, or from the secretion process itself. In this study, we generated transgenic mice with cardiac cell-specific overexpression of a secretion-defective mutant of Thbs4 to evaluate its exclusive intracellular and secretion-dependent functions. Like wild-type Thbs4, the secretion-defective mutant upregulates the adaptive ER stress response and expands the ER and intracellular vesicles in cardiomyocytes. However, only the secretion-defective Thbs4 mutant produces cardiomyopathy with sarcolemmal weakness and rupture that is associated with reduced adhesion-forming glycoproteins in the membrane. Similarly, deletion of Thbs4 in the mdx mouse model of Duchenne muscular dystrophy enhances cardiomyocyte membrane instability and cardiomyopathy. Finally, overexpression of the secretion-defective Thbs4 mutant in Drosophila, but not wild-type Thbs4, impaired muscle function and sarcomere alignment. These results suggest that transit through the secretory pathway is required for Thbs4 to augment sarcolemmal stability, while ER stress induction and vesicular expansion mediated by Thbs4 are exclusively intracellular processes.