One-year intradialytic leg exercises with resistance bands and fat mass increase in elderly hemodialysis patients: a retrospective study.

BACKGROUND: Intradialytic exercises are recommended to be available as a treatment for enhancing physical functioning. However, there have been few reports which evaluated the results of long-term mild intradialytic exercises in elderly patients. The purpose of this study is to investigate the changes in body weight, body composition, and laboratory data in elderly hemodialysis patients after 1-year intradialytic leg exercises with resistance bands. METHODS: A retrospective study. Twenty-one outpatients, aged 65 or older (mean ± SD, 75.2 ± 5.1 years), received intradialytic leg exercises with resistance bands for a year were analyzed. The values of dry weight, body composition, and laboratory data were collected from the year-ago period, at baseline and 1 year after baseline. Fat and muscle mass were evaluated by using a multi-frequency bioimpedance device. RESULTS: Physical performance changed and body weight increased after 1-year resistance band exercises. However, the participants gained fat mass, not muscle mass. Although the changes in biochemical data related to protein intake were equivocal, triglyceride levels increased significantly after 1-year exercises. An elevation in serum creatinine levels was observed, even if solute clearance increased significantly. CONCLUSIONS: One-year intradialytic leg exercises with resistance bands may have a potential clinical benefit for body mass index even in elderly hemodialysis patients. However, optimal dietary modification is needed to achieve a balanced increase of muscle and fat mass. An increase of serum creatinine levels does not always mean muscle mass hypertrophy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s41100-021-00341-z.

Two distinct mechanisms target the autophagy-related E3 complex to the pre-autophagosomal structure.

In autophagy, Atg proteins organize the pre-autophagosomal structure (PAS) to initiate autophagosome formation. Previous studies in yeast revealed that the autophagy-related E3 complex Atg12-Atg5-Atg16 is recruited to the PAS via Atg16 interaction with Atg21, which binds phosphatidylinositol 3-phosphate (PI3P) produced at the PAS, to stimulate conjugation of the ubiquitin-like protein Atg8 to phosphatidylethanolamine. Here, we discover a novel mechanism for the PAS targeting of Atg12-Atg5-Atg16, which is mediated by the interaction of Atg12 with the Atg1 kinase complex that serves as a scaffold for PAS organization. While autophagy is partially defective without one of these mechanisms, cells lacking both completely lose the PAS localization of Atg12-Atg5-Atg16 and show no autophagic activity. As with the PI3P-dependent mechanism, Atg12-Atg5-Atg16 recruited via the Atg12-dependent mechanism stimulates Atg8 lipidation, but also has the specific function of facilitating PAS scaffold assembly. Thus, this study significantly advances our understanding of the nucleation step in autophagosome formation.

USP19-Mediated Deubiquitination Facilitates the Stabilization of HRD1 Ubiquitin Ligase.

In the endoplasmic reticulum (ER), misfolded and unfolded proteins are eliminated by a process called ER-associated protein degradation (ERAD) in order to maintain cell homeostasis. In the ERAD pathway, several ER-localized E3 ubiquitin ligases target ERAD substrate proteins for ubiquitination and subsequent proteasomal degradation. However, little is known about how the functions of the ERAD ubiquitin ligases are regulated. Recently, USP19, an ER-anchored deubiquitinating enzyme (DUB), has been suggested to be involved in the regulation of ERAD. In this study, HRD1, an ERAD ubiquitin ligase, is shown to be a novel substrate for USP19. We demonstrate that USP19 rescues HRD1 from proteasomal degradation by deubiquitination of K48-linked ubiquitin chains. In addition, the altered expression of USP19 affects the steady-state levels of HRD1. These results suggest that USP19 regulates the stability of HRD1 and provide insight into the regulatory mechanism of the ERAD ubiquitin ligases.

Ubiquitin-specific protease 19 regulates the stability of the E3 ubiquitin ligase MARCH6.

Ubiquitin-specific protease (USP)19 is a recently identified deubiquitinating enzyme (DUB) having multiple splice variants and cellular functions. One variant encodes an endoplasmic reticulum (ER)-anchored DUB that rescues misfolded transmembrane proteins from ER-associated degradation (ERAD), but the underlying mechanism remains to be elucidated. Here, we show that USP19 interacts with the ERAD-associated E3 ubiquitin ligase MARCH6. Overexpression of USP19 delayed the degradation of MARCH6, leading to an increase in its protein level. In contrast, USP19 depletion resulted in decreased expression of MARCH6. We also show that USP19 overexpression reduced ubiquitination of MARCH6, while its knockdown had the opposite effect. In particular, USP19 was found to protect MARCH6 by deubiquitination from the p97-dependent proteasomal degradation. In addition, USP19 knockdown leads to increased expression of mutant ABCB11, an ERAD substrate of MARCH6. Moreover, USP19 is itself subjected to endoproteolytic processing by DUB activity, and the processing cleaves off an N-terminal cytoplasmic region of unknown function. However, elimination of this processing had no evident effect on MARCH6 stabilization. These results suggest that USP19 is involved in the regulation of ERAD by controlling the stability of MARCH6 via deubiquitination.