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Voltage-gated ClC-2 channels are essential for chloride homeostasis. Complete knockout of mouse ClC-2 leads to testicular degeneration and neuronal myelin vacuolation. Gain-of-function and loss-of-function mutations in the ClC-2-encoding human CLCN2 gene are linked to the genetic diseases aldosteronism and leukodystrophy, respectively. The protein homeostasis (proteostasis) mechanism of ClC-2 is currently unclear. Here, we aimed to identify the molecular mechanism of endoplasmic reticulum-associated degradation of ClC-2, and to explore the pathophysiological significance of disease-associated anomalous ClC-2 proteostasis. In both heterologous expression system and native neuronal and testicular cells, ClC-2 is subject to significant regulation by cullin-RING E3 ligase-mediated polyubiquitination and proteasomal degradation. The cullin 4 (CUL4)-damage-specific DNA binding protein 1 (DDB1)-cereblon (CRBN) E3 ubiquitin ligase co-exists in the same complex with and promotes the degradation of ClC-2 channels. The CRBN-targeting immunomodulatory drug lenalidomide and the cullin E3 ligase inhibitor MLN4924 promotes and attenuates, respectively, proteasomal degradation of ClC-2. Analyses of disease-related ClC-2 mutants reveal that aldosteronism and leukodystrophy are associated with opposite alterations in ClC-2 proteostasis. Modifying CUL4 E3 ligase activity with lenalidomide and MLN4924 ameliorates disease-associated ClC-2 proteostasis abnormality. Our results highlight the significant role and therapeutic potential of CUL4 E3 ubiquitin ligase in regulating ClC-2 proteostasis.

Feeding and resistance exercise stimulate myofibrillar protein synthesis (MPS) rates in healthy adults. This anabolic characterization of "healthy adults" has been namely focused on males. Therefore, the purpose of this study was to examine the temporal responses of MPS and anabolic signaling to resistance exercise alone or combined with the ingestion of protein in postmenopausal females and compare postabsorptive rates with young females. Sixteen females [60 ± 7 yr; body mass index (BMI) = 26 ± 12 kg·m−2] completed an acute bout of unilateral resistance exercise before consuming either: a fortified whey protein supplement (WHEY) or water. Participants received primed continuous infusions of L-[ring-13C6]phenylalanine with bilateral muscle biopsies before and after treatment ingestion at 2 h and 4 h in nonexercised and exercised legs. Resistance exercise transiently increased MPS above baseline at 0–2 h in the water condition (P = 0.007). Feeding after resistance exercise resulted in a late phase (2–4 h) increase in MPS in the WHEY condition (P = 0.005). In both conditions, resistance exercise did not enhance the cumulative (0–4 h) MPS response. In the nonexercised leg, MPS did not differ at 0–2 h, 2–4 h, or 0–4 h of the measurement periods (all, P > 0.05). Likewise, there were no changes in the phosphorylation of p70S6K, AMPKα, or total and phosphorylated yes-associated protein on Ser127. Finally, postabsorptive MPS was lower in premenopausal versus postmenopausal females (P = 0.023). Our results demonstrate that resistance exercise-induced changes in MPS are temporally regulated, but do not result in greater cumulative (0–4 h) MPS in postmenopausal women. NEW & NOTEWORTHY: An adequate quality and quantity of skeletal muscle is relevant to support physical performance and metabolic health. Muscle protein synthesis (MPS) is an established remodeling marker, which can be hypertrophic or nonhypertrophic. Importantly, protein ingestion and resistance exercise are two strategies that support healthy muscle by stimulating MPS. Our study shows postmenopause modulates baseline MPS that may diminish the MPS response to the fundamental anabolic stimuli of protein ingestion and resistance exercise in older females. [ABSTRACT FROM AUTHOR]

Introduction: Patients with kidney failure undergoing maintenance hemodialysis (HD) therapy are routinely counseled to reduce dietary sodium intake to ameliorate sodium retention, volume overload, and hypertension. However, low‐sodium diet trials in HD are sparse and indicate that dietary education and behavioral counseling are ineffective in reducing sodium intake. This study aimed to determine whether 4 weeks of low‐sodium, home‐delivered meals in HD patients reduces interdialytic weight gain (IDWG). Secondary outcomes included changes in dietary sodium intake, thirst, xerostomia, blood pressure, volume overload, and muscle sodium concentration. Methods: Twenty HD patients (55 ± 12 years, body mass index [BMI] 40.7 ± 16.6 kg/m2) were enrolled in this study. Participants followed a usual (control) diet for the first 4 weeks followed by 4 weeks of three low‐sodium, home‐delivered meals per day. We measured IDWG, hydration status (bioimpedance), standardized blood pressure (BP), food intake (3‐day dietary recall), and muscle sodium (magnetic resonance imaging) at baseline (0 M), after the 4‐week period of usual diet (1 M), and after the meal intervention (2 M). Findings: The low‐sodium meal intervention significantly reduced IDWG when compared to the control period (−0.82 ± 0.14 kg; 95% confidence interval, −0.55 to −1.08 kg; P < 0.001). There were also 1 month (1 M) to 2 month (2 M) reductions in dietary sodium intake (−1687 ± 297 mg; P < 0.001); thirst score (−4.4 ± 1.3; P = 0.003), xerostomia score (−6.7 ± 1.9; P = 0.002), SBP (−18.0 ± 3.6 mmHg; P < 0.001), DBP (−5.9 ± 2.0 mmHg; P = 0.008), and plasma phosphorus −1.55 ± 0.21 mg/dL; P = 0.005), as well as a 0 M to 2 M reduction in absolute volume overload (−1.08 ± 0.33 L; P = 0.025). However, there were no significant changes in serum or tissue sodium (all P > 0.05). Discussion: Low‐sodium, home‐meal delivery appears to be an effective method for improving volume control and blood pressure in HD patients. Future studies with larger sample sizes are needed to examine the long‐term effects of home‐delivered meals on these outcomes and to assess cost‐effectiveness. [ABSTRACT FROM AUTHOR]