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Aims: The objective of this umbrella review and meta‐analysis was to evaluate the effect of diabetes on risk of dementia, as well as the mitigating effect of antidiabetic treatments. Materials and Methods: We conducted a systematic umbrella review on diabetes and its treatment, and a meta‐analysis focusing on treatment. We searched MEDLINE/PubMed, Embase, PsycINFO, CINAHL and the Cochrane Library for systematic reviews and meta‐analyses assessing the risk of cognitive decline/dementia in individuals with diabetes until 2 July 2023. We conducted random‐effects meta‐analyses to obtain risk ratios and 95% confidence intervals estimating the association of metformin, thiazolidinediones, pioglitazone, dipeptidyl peptidase‐4 inhibitors, α‐glucosidase inhibitors, meglitinides, insulin, sulphonylureas, glucagon‐like peptide‐1 receptor agonists (GLP1RAs) and sodium‐glucose cotransporter‐2 inhibitors (SGLT2is) with risk of dementia from cohort/case‐control studies. The subgroups analysed included country and world region. Risk of bias was assessed with the AMSTAR tool and Newcastle‐Ottawa Scale. Results: We included 100 reviews and 27 cohort/case‐control studies (N = 3 046 661). Metformin, thiazolidinediones, pioglitazone, GLP1RAs and SGLT2is were associated with significant reduction in risk of dementia. When studies examining metformin were divided by country, the only significant effect was for the United States. Moreover, the effect of metformin was significant in Western but not Eastern populations. No significant effect was observed for dipeptidyl peptidase‐4 inhibitors, α‐glucosidase inhibitors, or insulin, while meglitinides and sulphonylureas were associated with increased risk. Conclusions: Metformin, thiazolidinediones, pioglitazone, GLP1RAs and SGLT2is were associated with reduced risk of dementia. More longitudinal studies aimed at determining their relative benefit in different populations should be conducted. [ABSTRACT FROM AUTHOR]

Sundaram P, Pang Z, Miao M, Yu L, Wing SS. USP19-deubiquitinating enzyme regulates levels of major myofibrillar proteins in L6 muscle cells. Am J Physiol Endocrinol Metab 297: E1283-E1290, 2009. First published September 22, 2009; doi: 10.1152/ajpendo.00409.2009.--The ubiquitin-proteasome system plays an important role in the degradation of myofibrillar proteins that occurs in muscle wasting. Many studies have demonstrated the importance of enzymes mediating conjugation of ubiquitin. However, little is known about the role of deubiquitinating enzymes. We previously showed that the USP19- deubiquitinating enzyme is induced in atrophying skeletal muscle (Combaret L, Adegoke OA, Bedard N, Baracos V, Attaix D, Wing SS. Am J Physiol Endocrinol Metab 288: E693-E700, 2005). To further explore the role of USP 19, we used small interfering RNA (siRNA) in L6 muscle cells. Lowering USP19 by 70-90% in myotubes resulted in a 20% decrease in the rate of proteolysis and an 18% decrease in the rate of protein synthesis, with no net change in protein content. Despite the decrease in overall synthesis, there were ~1.5-fold increases in protein levels of myosin heavy chain (MHC), actin, and troponin T and a ~2.5-fold increase in tropomyosin. USP19 depletion also increased MHC and tropomyosin mRNA levels, suggesting that this effect is due to increased transcription. Consistent with this, USP19 depletion increased myogenin protein and mRNA levels approximately twofold. Lowering myogenin using siRNA prevented the increase in MHC and tropomyosin upon USP19 depletion, indicating that myogenin mediated the increase in myofibrillar proteins. Dexamethasone treatment lowered MHC and increased USP19. Depletion of USP19 reversed the dexamethasone suppression of MHC. These studies demonstrate that USP19 modulates transcription of major myofibrillar proteins and indicate that the ubiquitin system not only mediates the increased protein breakdown but is also involved in the decreased protein synthesis in atrophying skeletal muscle. ubiquitin-specific processing protease doi: 10.1152/ajpendo.00409.2009.

Since maximum anabolism occurs postprandially, we developed a simulated fed state with clamped hyperinsulinemia, physiological hyperglycemia, and hyperaminoacidemia (Hyper-3) and explored muscle cellular mechanisms. Whole body [1-[sup.13]C]leucine and [3-[sup.3]H]glucose kinetics in healthy men were compared between hyperinsulinemic, euglycemic, isoaminoacidemic (Hyper-1, n = 10) and Hyper-3 (n = 9) clamps. In Hyper-3 vs. Hyper-1, nonoxidative leucine [R.sub.d] [rate of disappearance (synthesis)] was stimulated more (45 [+ or -] 4 vs. 24 [+ or -] 4 [micro]mol/min, P < 0.01) and endogenous [R.sub.a] [rate of appearance (breakdown)] was inhibited similarly; hence net balance increased more (86 [+ or -] 6 vs. 49 [+ or -] 2 [micro]mol/min, P < 0.001). Glucose [R.sub.d] was similar; thus Hyper-3 metabolic clearance rate (331 [+ or -] 23 vs. 557 [+ or -] 41 ml/min, P < 0.0005) and [R.sub.d]/insulin (M, 0.65 [+ or -] 0.10 vs. 1.25 [+ or -] 0.10 mg x [min.sup.-1] x [pmol.sup.-1] x 1, P < 0.001) were less, despite higher insulin (798 [+ or -] 74 vs. 450 [+ or -] 24 pmol/l, P < 0.005). In vastus lateralis muscle biopsies, phosphorylation of Akt (P = 0.025), mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase (p[70.sup.S6K1]; P = 0.008), S6 (P = 0.049), and 4E-binding protein 1 (4E-BP1; P = 0.001) increased. With decreased eukaryotic initiation factor-4E (eIF4E) x 4E-BP1 complex (P = 0.01), these are consistent with increased roTOR complex 1 (mTORC1) signaling and translation initiation of protein synthesis. Although mRNA expression of ubiquitin, MAFbx 1, and MuRF-1 was unchanged, total ubiquitinated proteins decreased 20% (P < 0.01), consistent with proteolysis suppression. The Hyper-3 clamp increases whole body protein synthesis, net anabolism, and muscle protein translation initiation pathways and decreases protein ubiquitination. The main contribution of hyperaminoacidemia is stimulation of synthesis rather than inhibition of proteolysis, and it attenuates the expected increment of glucose disposal. translation initiation; ubiquitin pathway; leucine kinetics; glucose turnover; insulin resistance

Chronic or acute inflammation may participate in the etiology of cancer cachexia. To investigate the interaction between tumor and a secondary inflammatory stimulus on muscle wasting, rats with and without tumors (Yoshida ascites hepatoma) received low doses of endotoxin (LPS, 400 [micro]g/kg sc) or saline. Nitrogen balance was measured 24 h before and after LPS/saline. Epitrochlearis muscle was used to measure in vitro protein metabolism, and gastrocnemius muscle was used for quantification of the mRNA for components of the ubiquitin proteolyric pathway. The YAH reduced muscle mass (P = 0.002), increased muscle protein degradation (P = 0.042), and elevated mRNA expression of components of the ubiquirin proteolytic pathway (P < 0.01) including ubiquitin, ubiquitin-conjugating enzyme [E2.sub.14k], and ubiquitin ligases muscle RING Finger 1 and atrogin-1. Although the selected low dose of LPS had no impact on protein metabolism in control rats, LPS in rats bearing YAH caused weight loss (P = 0.0007), lowered nitrogen balance (P = muscle wasting; inflammation; ubiquitin proteolytic pathway

Ubiquitin-dependent proteolysis is activated in skeletal muscle atrophying in response to various catabolic stimuli. Previous studies have demonstrated activation of ubiquitin conjugation. Because ubiquitination can also be regulated by deubiquitinating enzymes, we used degenerate oligonucleotides derived from conserved sequences in the ubiquitin-specific protease (UBP) family of deubiquitinating enzymes in RT-PCR with skeletal muscle RNA to amplify putative deubiquitinating enzymes. We identified USP19, a 150-kDa deubiquitinating enzyme that is widely expressed in various tissues including skeletal muscle. Expression of USP19 mRNA increased by ~30-200% in rat skeletal muscle atrophying in response to fasting, streptozotocin-induced diabetes, dexamethasone treatment, and cancer. Increased mRNA levels during fasting returned to normal with refeeding, but 1 day later than the normalization of rates of proteolysis and coincided instead with recovery of muscle mass. Indeed, in all catabolic treatments, USP19 mRNA was inversely correlated with muscle mass and provided an index of muscle mass that may be useful in many pathological conditions, using small human muscle biopsies. The increased expression of this deubiquitinating enzyme under conditions of increased proteolysis suggests that it may play a role in regeneration of free ubiquitin either coincident with or after proteasome-mediated degradation of substrates. USP19 may also be involved in posttranslational processing of polyubiquitin produced de novo in response to induction of the polyubiquitin genes seen under these conditions. Deubiquitinating enzymes thus appear involved in muscle wasting and implicate a widening web of regulation of genes in the ubiquitin system in this process. deubiquitinating enzyme; ubiquitin-proteasome-dependent proteolysis; muscle wasting; proteolysis

Heart failure is often characterized by skeletal muscle atrophy. The mechanisms underlying muscle wasting, however, are not fully understood. We studied 30 Dahl salt-sensitive rats (10 male, 20 female) fed either a high-salt (HS; n = 15) or a low-salt (LS; n = 15) diet. This strain develops cardiac hypertrophy and failure when fed a HS diet. LS controls were matched to HS rats for gender and duration of diet. Body mass, food intake, and muscle mass and composition were measured. Skeletal muscle protein synthesis was measured by isotope dilution. An additional group of 27 rats (HS, n = 16; LS; n = 11) were assessed for expression of genes regulating protein breakdown and apoptosis. Gastrocnemius and plantaris muscles weighed less (16 and 22%, respectively) in HS than in LS rats (P < 0.01). No differences in soleus or tibialis anterior weights were found. Differences in muscle mass were abolished after data were expressed relative to body size, because HS rats tended (P = 0.094) to weigh less. Lower body mass in HS rats was related to a 16% reduction (P < 0.01) in food intake. No differences in muscle protein or DNA content, the protein-to-DNA ratio, or muscle protein synthesis were found. Finally, no differences in skeletal muscle gene expression were found to suggest increased protein breakdown or apoptosis in HS rats. Our results suggest that muscle wasting in this model of heart failure is not associated with alterations in skeletal muscle metabolism. Instead, muscle atrophy was related to reduced body weight secondary to decreased food intake. These findings argue against the notion that heart failure is characterized by a skeletal muscle myopathy that predisposes to atrophy. atrophy; isotope; ubiquitin proteasome pathway; cytokine

Activated skeletal muscle proteolysis in catabolic states has been linked to an upregulation of the ATP-ubiquitin-dependent proteolytic system. Previous studies suggested that the N-end rule pathway is primarily responsible for the bulk of skeletal muscle proteolysis. The activity of this pathway is dependent on the 14-kDa ubiquitin-conjugating enzyme [E2.sub.14k] (HR6B) and the ubiquitin protein ligase Ubr1. To address the requirement of [E2.sub.14k] in muscle proteolysis, we examined muscle protein metabolism in wild-type (WT) mice and mice lacking the [E2.sub.14k] gene (KO) in fed and fasted (48 h) states. Baseline body weight, muscle mass, and protein content were similar, and these parameters decreased similarly upon fasting in the two genotypes. There were also no effects of genotype on the rate of proteolysis in soleus muscle. The fasting-induced increase in the amount of ubiquitinated proteins was the same in WT and KO mice. The absence of any significant effect of loss of [E2.sub.14k] function was not due to a compensatory induction of the closely related isoform HR6A. Total intracellular concentration of [E2.sub.14k] and HR6A in the WT mice was 290 [+ or -] 40 nM, but the level in the KO mice (reflecting the level of HR6A) was 110 [+ or -] 9 nM. This value is about threefold the apparent Michaelis-Menten constant ([K.sub.m]) of [E2.sub.14k] (~40 nM) for stimulating conjugation in muscle extracts. Because the HR6A isoform has a [K.sub.m] of 16 nM for stimulating conjugation, the HR6A levels in the muscles of KO mice appear sufficient for supporting conjugation mediated by this pathway during fasting. ubiquitin conjugation; starvation; muscle wasting; proteasome; muscle incubation

The activity of the ubiquitin-dependent proteolytic system in differentiated tissues under basal conditions remains poorly explored. We measured rates of ubiquitination in rat tissue extracts. Accumulation of ubiquitinated proteins increased in the presence of ubiquitin aldehyde, indicating that deubiquitinating enzymes can regulate ubiquitination. Rates of ubiquitination varied fourfold, with the highest rate in the testis. We tested whether ubiquitin-activating enzyme (E1) or ubiquitin-conjugating enzymes (E2s) could be limiting for conjugation. Immunodepletion of the E2s UBC2 or UBC4 lowered rates of conjugation similarly. Supplementation of extracts with excess UBC2 or UBC4, but not E1, stimulated conjugation. However, UBC2-stimulated rates of ubiquitination still differed among tissues, indicating that tissue differences in E3s or substrate availability may also be rate controlling. UBC2 and UBC4 stimulated conjugation half-maximally at concentrations of 10-50 and 28-44 nM, respectively. Endogenous tissue levels of UBC2, but not UBC4, appeared saturating for conjugation, suggesting that in vivo modulation of UBC4 levels can likely control ubiquitin conjugation. Thus the pool of ubiquitin conjugates and therefore the rate of degradation of proteins by this system may be controlled by E2s, E3s, and isopeptidases. The regulation of the ubiquitin pathway appears complex, but precise. proteolysis; proteasome; deubiquitinating enzymes; isopeptidases

A study of 14-kDa ubiquitin-conjugating enzyme and its structure suggests a direct hormonal modulation of the gene in the ubiquitin system, which has a role in the metabolic response to fasting in rat skeletal muscle. Fasting leads to a rise in proteolysis in rat skeletal muscle, which is related to raised amounts of ubiquitin-protein conjugates. The gene encoding the 14-kDa ubiquitin-conjugating enzyme changes with respect to alterations in amounts of ubiquitinated proteins and proteolysis rate.

The effects of glucocorticoid-activated proteolytic pathways in skeletal muscles during fasting were studied in rat leg muscles. Fasting produced a 250% increase in nonlysosomal ATP-dependent process along with a significant increase ubiquitin (Ub) messenger ribonucleic acid (mRNA) levels which was not observed in the adrenolectomized (ADX) rats. Dexamethasone injections in fasted ADX rats raised Ub mRNA in six hours suggesting that glucocorticoids trigger ATP-Ub-dependent proteolytic pathways during fasting.

Osteoporosis and sarcopenia are common comorbid diseases, yet their shared mechanisms are largely unknown. We found that genetic variation near FAM210A was associated, through large genome-wide association studies, with fracture, bone mineral density (BMD), and appendicular and whole body lean mass, in humans. In mice, Fam210a was expressed in muscle mitochondria and cytoplasm, as well as in heart and brain, but not in bone. Grip strength and limb lean mass were reduced in tamoxifen-inducible Fam210a homozygous global knockout mice (TFam210a-/-), and in tamoxifen-inducible Fam210 skeletal muscle cell-specific knockout mice (TFam210aMus-/-). Decreased BMD, bone biomechanical strength, and bone formation, and elevated osteoclast activity with microarchitectural deterioration of trabecular and cortical bones, were observed in TFam210a-/- mice. BMD of male TFam210aMus-/- mice was also reduced, and osteoclast numbers and surface in TFam210aMus-/- mice increased. Microarray analysis of muscle cells from TFam210aMus-/- mice identified candidate musculoskeletal modulators. FAM210A, a novel gene, therefore has a crucial role in regulating bone structure and function, and may impact osteoporosis through a biological pathway involving muscle as well as through other mechanisms. [ABSTRACT FROM AUTHOR]