OBJECTIVE To assess the effects of annuloplasty rings (ARs) on anterior mitral leaflet (AML) dimensions. METHODS Sixteen radiopaque markers were sutured evenly spaced over the surface of the AML in 57 sheep. Size 28 mm Cosgrove (n=11), rigid saddle-shaped AR (RSAR) (n=12), Physio (n=12), IMR-ETlogix (n=10) and GeoForm (n=12) rings were implanted in a releasable fashion. Under acute open-chest conditions, 4-D marker coordinates were measured using biplane videofluoroscopy with the AR inserted and after AR release. Septal-lateral and commissure-commissure dimensions were calculated from opposing marker pairs on the septal-lateral and commissure-commissure aspect of the AML at end-diastole (ED) and end-systole (ES). To assess changes in AML shape, a “planarity index” was assessed by calculating the root mean square values as distances of the 16 AML markers to a best fit AML plane at ES. RESULTS At ED, AML septal-lateral and commissure-commissure dimensions did not change with Cosgrove compared to Control, while RSAR, Physio, IMR-ETlogix and GeoForm reduced AML commissure-commissure, but not septal-lateral AML dimensions. At ES, the septal-lateral AML dimension was smaller with IMR-ETlogix and GeoForm, but did not change with Cosgrove, RSAR and Physio. AML shape was unchanged in all five groups. CONCLUSIONS With no changes in AML planarity, the 4 complete, rigid rings (RSAR, Physio, IMR-ETlogix, and GeoForm) reduced the AML commissure-commissure dimension at ED. IMR-ETlogix and GeoForm decreased the septal-lateral AML dimension at ES, probably due to inherent disproportionate downsizing. These changes in AML geometry could perturb the stress patterns, which in theory may affect repair durability.

Skeletal muscles are dynamic tissues that possess regenerative abilities, which require multiple processes and regulatory factors. Ubiquitin C-Terminal Hydrolase L1 (UCHL1), which is primarily expressed in neuronal tissues, was upregulated in skeletal muscles in disease conditions but its functional role in skeletal muscles is unknown. Using mouse myoblast cells C2C12 as an in vitro model, this study reported that UCHL1 elicits different regulation in myoblast cell proliferation and differentiation. We first observed that UCHL1 protein level was continuously declined during cell differentiation. Gene knockdown of UCHL1 by siRNA resulted in a significant decrease in cell proliferation but marked acceleration of cell differentiation and myotube formation. Meanwhile, UCHL1 gene knockdown upregulated myogenic factors myoD and Myogenin (MyoG). In mice, UCHL1 was significantly upregulated in denervated skeletal muscle. Overall, these novel data suggest that UCHL1 may play a role in myogenesis by promoting myoblast proliferation and inhibiting differentiation.

Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) is a deubiquitinating enzyme, which is highly expressed in neuronal cells. Previous studies have indicated that UCHL1 is involved in cognitive function, neurodegenerative diseases, and neuromuscular junction development. Acetylcholine (Ach) is a critical neurotransmitter in these functions. Yet, the effect of UCHL1 on the cholinergic system has not been reported. In this study, using a cholinergic neuronal cell line, SN56, as an in vitro model, we detected the physical interaction of UCHL1 and high affinity choline transporter (CHT), which is a key protein regulating Ach re-synthesis. Reduction of UCHL1 by siRNA gene knockdown significantly increased poly-ubiquitinated CHT and decreased native CHT protein level, but did not affect CHT mRNA expression. Biotinylation assay showed that UCHL1 is localized only in the cytosol of the cells and that the gene knockdown of UCHL1 significantly reduced cytosolic CHT but had no significant effect on membrane CHT level. These data provide novel and potentially important evidence that UCHL1 may play a role in the regulation of cholinergic function by affecting CHT ubiquitination and degradation.

Suppressed parasympathetic function is commonly present in cardiovascular diseases, aging, obesity, and various other health conditions. Impaired parasympathetic action is known as a detrimental factor and contributes to the adverse outcomes in these conditions. However, the underlying mechanisms remain to be fully addressed. In this study, using high-fat diet (HFD)-induced obese mice as a model, the potential peripheral mechanisms underlying the impaired parasympathetic vagal control of the heart was examined. The HFD induced obesity and metabolic disorder in mice. These obese mice exhibited an attenuated response in heart rate to vagal stimulation, indicating impairment of peripheral parasympathetic activity in the heart. In cholinergic function-related proteins in the atria, protein levels of choline transporter and vesicular acetylcholine transporter were not decreased but increased, and type 2 muscarinic receptors showed a trend toward a reduction in HFD mice atria as compared with regular diet (RD) mice controls. While the protein level of acetylcholinesterase was not different, butyrylcholinesterase (BChE) protein level showed a twofold increase in HFD mice atria as compared with RD mice. Functionally, inhibition of BChE activity partially and significantly improved the attenuated response in heart rate to vagal stimulation in HFD mice. Collectively, these data suggest that increased BChE activity in the atria may contribute to the decreased parasympathetic function in HFD-induced obese mice.

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