Wakabayashi & Daimon cardiometabolic index as an indicator to assess risk in adults. A systematic review / Índice cardiometabólico de Wakabayashi y Daimon como indicador para evaluar el riesgo en adultos. Una revisión sistemática

Objective To analyze the Wakabayashi & Daimon (2015) equation, as a predictive indicator of cardiometabolic diseases and its comparison with other indices. Design A systematic review was carried out between January and March 2023, according to the PRISMA statement. Data source Scopus, Web of Science, and PubMed databases were reviewed using “cardiometabolic index” (CMI) as the search term. Study selection The following inclusion criteria were determined: studies in adults with cardiometabolic diseases using the Wakabayashi & Daimon (2015) CMI formula in different populations; studies that validate or compare the equation or that demonstrate the effects of the intervention. Data extraction Of the 11 selected articles, the characteristics of the population, type of study, indicators for the validation of the CMI, the reported statistics and the conclusions that were recorded in a comparative table were obtained. Results and conclusions Odds ratio, hazard ratio, sensitivity, and specificity were used to assess associations, risk, effectiveness, and validity of the tests, indicating favorable relationships between the factors analyzed and the results obtained. Validation and probabilistic analysis of the CMI were performed against diverse diseases such as obesity [Man >60y=AUC=0.90 (0.75–1.00) (p=0.01), Se=100, Sp=81.8, YI=0.82 and OR 4.66 and Women >60y=AUC=0.95 (0.88–1.00), p=0.001, Se=90.0, Sp=100, YI=0.90 and OR=36.27]; cardiovascular diseases [AUC=0.617, Se=0.675, Sp=0.509; HR=1.48 (1.33, 1.65), p=<0.001], among others. In conclusion CMI is a new utility index that broadly identifies the presence of risk that leads to cardiometabolic diseases in adults. (AU)

Objetivo Analizar la ecuación de Wakabayashi et al. del 2015 como indicador de predicción de enfermedades cardiometabólicas y su comparación con otros índices.Diseño Se realizó una revisión sistemática entre enero y marzo del 2023, de acuerdo con la declaración PRISMA. Fuente de datos Se revisaron las bases de datos Scopus, Web of Science y PubMed utilizando «índice cardiometabólico» (ICM) como término de búsqueda. Selección de los estudios Se determinaron los siguientes criterios de inclusión: estudios en adultos con enfermedades cardiometabólicas que utilizaron la fórmula ICM de Wakabayashi et al. en diferentes poblaciones; que validaran o compararan la ecuación o que demostraran los efectos de la intervención. Extracción de datos De los 11 artículos seleccionados, se obtuvieron las características de la población, tipo de estudio, indicadores para la validación del ICM, la estadística reportada y las conclusiones que se registraron en una tabla comparativa. Resultados y conclusiones Para evaluar las asociaciones, el riesgo, la efectividad y la validez de las pruebas se utilizaron odds ratio (OR), hazard ratio (HR), sensibilidad y especificidad, indicando relaciones favorables entre los factores analizados y los resultados obtenidos. La validación y el análisis probabilístico del ICM se realizaron frente a diversas enfermedades como obesidad (hombres >60 años=AUC=0,90 [0,75-1,00], [p=0,01], Se=100, Sp=81,8, YI=0,82 y OR 4,66; y mujeres >60 años=AUC=0,95 [0,88-1,00], p=0,001, Se=90,0, Sp=100, YI=0,90 y OR=36,27); enfermedades cardiovasculares (AUC=0,617, Se=0,675, Sp=0,509; HR=1,48 [1,33, 1,65] p≤0,001), entre otros. En conclusión, el ICM es un nuevo índice de utilidad que identifica ampliamente la presencia de riesgo para conducir a enfermedades cardiometabólicas en adultos. (AU)

Wakabayashi & Daimon cardiometabolic index as an indicator to assess risk in adults. A systematic review.

OBJECTIVE: To analyze the Wakabayashi & Daimon (2015) equation, as a predictive indicator of cardiometabolic diseases and its comparison with other indices. DESIGN: A systematic review was carried out between January and March 2023, according to the PRISMA statement. DATA SOURCE: Scopus, Web of Science, and PubMed databases were reviewed using "cardiometabolic index" (CMI) as the search term. STUDY SELECTION: The following inclusion criteria were determined: studies in adults with cardiometabolic diseases using the Wakabayashi & Daimon (2015) CMI formula in different populations; studies that validate or compare the equation or that demonstrate the effects of the intervention. DATA EXTRACTION: Of the 11 selected articles, the characteristics of the population, type of study, indicators for the validation of the CMI, the reported statistics and the conclusions that were recorded in a comparative table were obtained. RESULTS AND CONCLUSIONS: Odds ratio, hazard ratio, sensitivity, and specificity were used to assess associations, risk, effectiveness, and validity of the tests, indicating favorable relationships between the factors analyzed and the results obtained. Validation and probabilistic analysis of the CMI were performed against diverse diseases such as obesity [Man >60y=AUC=0.90 (0.75-1.00) (p=0.01), Se=100, Sp=81.8, YI=0.82 and OR 4.66 and Women >60y=AUC=0.95 (0.88-1.00), p=0.001, Se=90.0, Sp=100, YI=0.90 and OR=36.27]; cardiovascular diseases [AUC=0.617, Se=0.675, Sp=0.509; HR=1.48 (1.33, 1.65), p=<0.001], among others. In conclusion CMI is a new utility index that broadly identifies the presence of risk that leads to cardiometabolic diseases in adults.

GNIP1 E3 ubiquitin ligase is a novel player in regulating glycogen metabolism in skeletal muscle.

BACKGROUND: Glycogenin-interacting protein 1 (GNIP1) is a tripartite motif (TRIM) protein with E3 ubiquitin ligase activity that interacts with glycogenin. These data suggest that GNIP1 could play a major role in the control of glycogen metabolism. However, direct evidence based on functional analysis remains to be obtained. OBJECTIVES: The aim of this study was 1) to define the expression pattern of glycogenin-interacting protein/Tripartite motif containing protein 7 (GNIP/TRIM7) isoforms in humans, 2) to test their ubiquitin E3 ligase activity, and 3) to analyze the functional effects of GNIP1 on muscle glucose/glycogen metabolism both in human cultured cells and in vivo in mice. RESULTS: We show that GNIP1 was the most abundant GNIP/TRIM7 isoform in human skeletal muscle, whereas in cardiac muscle only TRIM7 was expressed. GNIP1 and TRIM7 had autoubiquitination activity in vitro and were localized in the Golgi apparatus and cytosol respectively in LHCN-M2 myoblasts. GNIP1 overexpression increased glucose uptake in LHCN-M2 myotubes. Overexpression of GNIP1 in mouse muscle in vivo increased glycogen content, glycogen synthase (GS) activity and phospho-GSK-3α/ß (Ser21/9) and phospho-Akt (Ser473) content, whereas decreased GS phosphorylation in Ser640. These modifications led to decreased blood glucose levels, lactate levels and body weight, without changing whole-body insulin or glucose tolerance in mouse. CONCLUSION: GNIP1 is an ubiquitin ligase with a markedly glycogenic effect in skeletal muscle.

Glucose and fructose have sugar-specific effects in both liver and skeletal muscle in vivo: a role for liver fructokinase.

We examined glucose and fructose effects on serine phosphorylation levels of a range of proteins in rat liver and muscle cells. For this, healthy adult rats were subjected to either oral glucose or fructose loads. A mini-array system was utilized to determine serine phosphorylation levels of liver and skeletal muscle proteins. A glucose oral load of 125 mg/100 g body weight (G 1/2) did not induce changes in phosphorylated serines of the proteins studied. Loading with 250 mg/100 g body weight of fructose (Fr), which induced similar glycemia levels as G 1/2, significantly increased serine phosphorylation of liver cyclin D3, PI3 kinase/p85, ERK-2, PTP2 and clusterin. The G 1/2 increased serine levels of the skeletal muscle proteins cyclin H, Cdk2, IRAK, total PKC, PTP1B, c-Raf 1, Ras and the ß-subunit of the insulin receptor. The Fr induced a significant increase only in muscle serine phosphorylation of PI3 kinase/p85. The incubation of isolated rat hepatocytes with 10 mM glucose for 5 min significantly increased serine phosphorylation of 31 proteins. In contrast, incubation with 10 mM fructose produced less intense effects. Incubation with 10 mM glucose plus 75 µM fructose counteracted the effects of the incubation with glucose alone, except those on Raf-1 and Ras. Less marked effects were detected in cultured muscle cells incubated with 10 mM glucose or 10 mM glucose plus 75 µM fructose. Our results suggest that glucose and fructose act as specific functional modulators through a general mechanism that involves liver-generated signals, like micromolar fructosemia, which would inform peripheral tissues of the presence of either glucose- or fructose-derived metabolites.

Glucose dependence of glycogen synthase activity regulation by GSK3 and MEK/ERK inhibitors and angiotensin-(1-7) action on these pathways in cultured human myotubes.

Glycogen synthase (GS) is activated by glucose/glycogen depletion in skeletal muscle cells, but the contributing signaling pathways, including the chief GS regulator GSK3, have not been fully defined. The MEK/ERK pathway is known to regulate GSK3 and respond to glucose. The aim of this study was to elucidate the GSK3 and MEK/ERK pathway contribution to GS activation by glucose deprivation in cultured human myotubes. Moreover, we tested the glucose-dependence of GSK3 and MEK/ERK effects on GS and angiotensin (1-7) actions on these pathways. We show that glucose deprivation activated GS, but did not change phospho-GS (Ser640/1), GSK3ß activity or activity-activating phosphorylation of ERK1/2. We then treated glucose-replete and -depleted cells with SB415286, U0126, LY294 and rapamycin to inhibit GSK3, MEK1/2, PI3K and mTOR, respectively. SB415286 activated GS and decreased the relative phospho-GS (Ser640/1) level, more in glucose-depleted than -replete cells. U0126 activated GS and reduced the phospho-GS (Ser640/1) content significantly in glucose-depleted cells, while GSK3ß activity tended to increase. LY294 inactivated GS in glucose-depleted cells only, without affecting relative phospho-GS (Ser640/1) level. Rapamycin had no effect on GS activation. Angiotensin-(1-7) raised phospho-ERK1/2 but not phospho-GSK3ß (Ser9) content, while it inactivated GS and increased GS phosphorylation on Ser640/1, in glucose-replete cells. In glucose-depleted cells, angiotensin-(1-7) effects on ERK1/2 and GS were reverted, while relative phospho-GSK3ß (Ser9) content decreased. In conclusion, activation of GS by glucose deprivation is not due to GS Ser640/1 dephosphorylation, GSK3ß or ERK1/2 regulation in cultured myotubes. However, glucose depletion enhances GS activation/Ser640/1 dephosphorylation due to both GSK3 and MEK/ERK inhibition. Angiotensin-(1-7) inactivates GS in glucose-replete cells in association with ERK1/2 activation, not with GSK3 regulation, and glucose deprivation reverts both hormone effects. Thus, the ERK1/2 pathway negatively regulates GS activity in myotubes, without involving GSK3 regulation, and as a function of the presence of glucose.

Muscle fiber atrophy and regeneration coexist in collagen VI-deficient human muscle: role of calpain-3 and nuclear factor-κB signaling.

Ullrich congenital muscular dystrophy (UCMD) is a common form of muscular dystrophy associated with defects in collagen VI. It is characterized by loss of individual muscle fibers and muscle mass and proliferation of connective and adipose tissues. We sought to investigate the mechanisms by which collagen VI regulates muscle cell survival, size, and regeneration and, in particular, the potential role of the ubiquitin-proteasome and calpain-proteolytic systems. We studied muscle biopsies of UCMD (n = 6), other myopathy (n = 12), and control patients (n = 10) and found reduced expression of atrogin-1, MURF1, and calpain-3 mRNAs in UCMD cases. Downregulation of calpain-3 was associated with changes in the nuclear immunolocalization of nuclear factor-κB. We also observed increased expression versus controls of regeneration markers at the protein and RNA levels. Satellite cell numbers did not differ in collagen VI-deficient muscle versus normal nonregenerating muscle, indicating that collagen VI does not play a key role in the maintenance of the satellite cell pool. Our results indicate that alterations in calpain-3 and nuclear factor-κB signaling pathways may contribute to muscle mass loss in UCMD muscle, whereas atrogin-1 and MURF1 are not likely to play a major role.

PGC-1α induces mitochondrial and myokine transcriptional programs and lipid droplet and glycogen accumulation in cultured human skeletal muscle cells.

The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) is a chief activator of mitochondrial and metabolic programs and protects against atrophy in skeletal muscle (skm). Here we tested whether PGC-1α overexpression could restructure the transcriptome and metabolism of primary cultured human skm cells, which display a phenotype that resembles the atrophic phenotype. An oligonucleotide microarray analysis was used to reveal the effects of PGC-1α on the whole transcriptome. Fifty-three different genes showed altered expression in response to PGC-1α: 42 upregulated and 11 downregulated. The main gene ontologies (GO) associated with the upregulated genes were mitochondrial components and processes and this was linked with an increase in COX activity, an indicator of mitochondrial content. Furthermore, PGC-1α enhanced mitochondrial oxidation of palmitate and lactate to CO(2), but not glucose oxidation. The other most significantly associated GOs for the upregulated genes were chemotaxis and cytokine activity, and several cytokines, including IL-8/CXCL8, CXCL6, CCL5 and CCL8, were within the most highly induced genes. Indeed, PGC-1α highly increased IL-8 cell protein content. The most upregulated gene was PVALB, which is related to calcium signaling. Potential metabolic regulators of fatty acid and glucose storage were among mainly regulated genes. The mRNA and protein level of FITM1/FIT1, which enhances the formation of lipid droplets, was raised by PGC-1α, while in oleate-incubated cells PGC-1α increased the number of smaller lipid droplets and modestly triglyceride levels, compared to controls. CALM1, the calcium-modulated δ subunit of phosphorylase kinase, was downregulated by PGC-1α, while glycogen phosphorylase was inactivated and glycogen storage was increased by PGC-1α. In conclusion, of the metabolic transcriptome deficiencies of cultured skm cells, PGC-1α rescued the expression of genes encoding mitochondrial proteins and FITM1. Several myokine genes, including IL-8 and CCL5, which are known to be constitutively expressed in human skm cells, were induced by PGC-1α.

Differential pattern of glycogen accumulation after protein phosphatase 1 glycogen-targeting subunit PPP1R6 overexpression, compared to PPP1R3C and PPP1R3A, in skeletal muscle cells.

BACKGROUND: PPP1R6 is a protein phosphatase 1 glycogen-targeting subunit (PP1-GTS) abundant in skeletal muscle with an undefined metabolic control role. Here PPP1R6 effects on myotube glycogen metabolism, particle size and subcellular distribution are examined and compared with PPP1R3C/PTG and PPP1R3A/G(M). RESULTS: PPP1R6 overexpression activates glycogen synthase (GS), reduces its phosphorylation at Ser-641/0 and increases the extracted and cytochemically-stained glycogen content, less than PTG but more than G(M). PPP1R6 does not change glycogen phosphorylase activity. All tested PP1-GTS-cells have more glycogen particles than controls as found by electron microscopy of myotube sections. Glycogen particle size is distributed for all cell-types in a continuous range, but PPP1R6 forms smaller particles (mean diameter 14.4 nm) than PTG (36.9 nm) and G(M) (28.3 nm) or those in control cells (29.2 nm). Both PPP1R6- and G(M)-derived glycogen particles are in cytosol associated with cellular structures; PTG-derived glycogen is found in membrane- and organelle-devoid cytosolic glycogen-rich areas; and glycogen particles are dispersed in the cytosol in control cells. A tagged PPP1R6 protein at the C-terminus with EGFP shows a diffuse cytosol pattern in glucose-replete and -depleted cells and a punctuate pattern surrounding the nucleus in glucose-depleted cells, which colocates with RFP tagged with the Golgi targeting domain of ß-1,4-galactosyltransferase, according to a computational prediction for PPP1R6 Golgi location. CONCLUSIONS: PPP1R6 exerts a powerful glycogenic effect in cultured muscle cells, more than G(M) and less than PTG. PPP1R6 protein translocates from a Golgi to cytosolic location in response to glucose. The molecular size and subcellular location of myotube glycogen particles is determined by the PPP1R6, PTG and G(M) scaffolding.

Expression of glycogen phosphorylase isoforms in cultured muscle from patients with McArdle's disease carrying the p.R771PfsX33 PYGM mutation.

BACKGROUND: Mutations in the PYGM gene encoding skeletal muscle glycogen phosphorylase (GP) cause a metabolic disorder known as McArdle's disease. Previous studies in muscle biopsies and cultured muscle cells from McArdle patients have shown that PYGM mutations abolish GP activity in skeletal muscle, but that the enzyme activity reappears when muscle cells are in culture. The identification of the GP isoenzyme that accounts for this activity remains controversial. METHODOLOGY/PRINCIPAL FINDINGS: In this study we present two related patients harbouring a novel PYGM mutation, p.R771PfsX33. In the patients' skeletal muscle biopsies, PYGM mRNA levels were ∼60% lower than those observed in two matched healthy controls; biochemical analysis of a patient muscle biopsy resulted in undetectable GP protein and GP activity. A strong reduction of the PYGM mRNA was observed in cultured muscle cells from patients and controls, as compared to the levels observed in muscle tissue. In cultured cells, PYGM mRNA levels were negligible regardless of the differentiation stage. After a 12 day period of differentiation similar expression of the brain and liver isoforms were observed at the mRNA level in cells from patients and controls. Total GP activity (measured with AMP) was not different either; however, the active GP activity and immunoreactive GP protein levels were lower in patients' cell cultures. GP immunoreactivity was mainly due to brain and liver GP but muscle GP seemed to be responsible for the differences. CONCLUSIONS/SIGNIFICANCE: These results indicate that in both patients' and controls' cell cultures, unlike in skeletal muscle tissue, most of the protein and GP activities result from the expression of brain GP and liver GP genes, although there is still some activity resulting from the expression of the muscle GP gene. More research is necessary to clarify the differential mechanisms of metabolic adaptations that McArdle cultures undergo in vitro.