Skeletal muscle proteomes reveal downregulation of mitochondrial proteins in transition from prediabetes into type 2 diabetes.
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ABSTRACT:
SUBMITTER: Ohman T
PROVIDER: S-EPMC8246593 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Sodium Fluoride (NaF) can change the expression of skeletal muscle proteins. Since skeletal muscle is rich in mitochondrial and contractile (sarcomeric) proteins, these proteins are sensitive to the effects of NaF, and the changes are dose-and time-dependent. In the current study, we have analysed the effect of high concentrations of NaF (80ppm) on mouse skeletal muscle at two different time points, i.e., 15 days and 60 days. At the end of the experimental time, the animals were sacrificed, skeletal muscles were isolated, and proteins were extracted and subjected to bioinformatic (Mass Spectrometric) analysis. The results were analysed based on changes in different mitochondrial complexes, contractile (sarcomeric) proteins, 26S proteasome, and ubiquitin-proteasome pathway. The results showed that the mitochondrial proteins of complex I, II, III, IV and V were differentially regulated in the groups treated with 80ppm of NaF for 15 days and 60 days. The network analysis indicated more changes in mitochondrial proteins in the group treated with the higher dose for 15 days rather than 60 days. Furthermore, differential expression of (sarcomeric) proteins, downregulation of 26S proteasome subunits, and differential expression in proteins related to the ubiquitin-proteasome pathway lead to muscle atrophy. The differential expression might be due to the adaptative mechanism to counteract the deleterious effects of NaF on energy metabolism. Data are available via ProteomeXchange with identifier PXD035014.
| S-EPMC9779014 | biostudies-literature
Project description:The rising prevalence of gestational diabetes mellitus (GDM) affects up to 18% of pregnant women with immediate and long-term metabolic consequences for both mother and infant. Abnormal glucose uptake and lipid oxidation are hallmark features of GDM prompting us to use an exploratory proteomics approach to investigate the cellular mechanisms underlying differences in skeletal muscle metabolism between obese pregnant women with GDM (OGDM) and obese pregnant women with normal glucose tolerance (ONGT). Functional validation was performed in a second cohort of obese OGDM and ONGT pregnant women. Quantitative proteomic analysis in rectus abdominus skeletal muscle tissue collected at delivery revealed reduced protein content of mitochondrial complex I (C-I) subunits (NDUFS3, NDUFV2) and altered content of proteins involved in calcium homeostasis/signaling (calcineurin A, ?1-syntrophin, annexin A4) in OGDM (n?=?6) vs. ONGT (n?=?6). Follow-up analyses showed reduced enzymatic activity of mitochondrial complexes C-I, C-III, and C-IV (-60-75%) in the OGDM (n?=?8) compared with ONGT (n?=?10) subjects, though no differences were observed for mitochondrial complex protein content. Upstream regulators of mitochondrial biogenesis and oxidative phosphorylation were not different between groups. However, AMPK phosphorylation was dramatically reduced by 75% in the OGDM women. These data suggest that GDM is associated with reduced skeletal muscle oxidative phosphorylation and disordered calcium homeostasis. These relationships deserve further attention as they may represent novel risk factors for development of GDM and may have implications on the effectiveness of physical activity interventions on both treatment strategies for GDM and for prevention of type 2 diabetes postpartum.
| S-EPMC4162568 | biostudies-literature
Project description:The objective of this study was to determine the role of maximum mitochondrial capacity on the variation in insulin sensitivity within a population of patients with type 2 diabetes mellitus (T2DM).Fifty-eight participants enrolled in a cross-sectional design: eight active controls [maximum aerobic capacity (VO(2max)) > 40 ml/kg · min], 17 healthy sedentary controls without a family history (FH-) and seven with a family history (FH+) of diabetes, four obese participants, and 21 patients with T2DM. Mitochondrial capacity was measured noninvasively using (31)P magnetic resonance spectroscopy of the vastus lateralis. Maximal ATP synthetic rate (ATP(max)) was determined from the rate of phosphocreatine (PCr) recovery after short-term isometric exercise.ATP(max) was lower (P < 0.001) in T2DM and higher (P < 0.001) in active as compared with healthy sedentary FH- (active, 1.01 ± 0.2; FH-, 0.7 ± 0.2; FH+, 0.6 ± 0.1; obese, 0.6 ± 0.1; T2DM, 0.5 ± 0.2 mm ATP/sec; ANOVA P < 0.0001). Insulin sensitivity, measured by euglycemic-hyperinsulinemic (80 mIU/m(2) · min) clamp was also reduced in T2DM (P < 0.001) (active, 12.0 ± 3.2; FH-, 7.8 ± 2.2; FH+, 6.8 ± 3.5; obese, 3.1 ± 1.0; T2DM, 3.4 ± 1.6; mg/kg estimated metabolic body size · min; ANOVA P < 0.0001). Unexpectedly, there was a broad range of ATP(max) within the T2DM population where 52% of subjects with T2DM had ATP(max) values that were within the range observed in healthy sedentary controls. In addition, 24% of the T2DM subjects overlapped with the active control group (range, 0.65-1.27 mm ATP/sec). In contrast to the positive correlation between ATP(max) and M-value in the whole population (r(2) = 0.35; P < 0.0001), there was no correlation between ATP(max) and M-value in the patients with T2DM (r(2) = 0.004; P = 0.79).Mitochondrial capacity is not associated with insulin action in T2DM.
| S-EPMC3070252 | biostudies-literature
Project description:Background: Type 2 Diabetes (T2D) is a major concern among Asian Indians, not least because many develop T2D at despite having a normal BMI (body mass index), and with relatively low body fat. Asian Indians are also generally considered to have relatively low skeletal muscle mass and strength, this has not been explored in the context of T2D. Aim: The present study aimed to compare skeletal muscle mass, function and contractile quality (strength/mass) between healthy controls, those with prediabetes (PD) as well as T2D middle-aged non-obese Asian Indians. Methods: Adult males between the age of 20-50 years, consisting of healthy controls (n = 44), PD (n = 125) and T2D (n = 55) were studied. Skeletal muscle mass was measured using Dual X-ray Absorptiometry (DXA). Isometric and dynamic muscle function was measured using an isokinetic dynamometer (at 0, 60, 120, 180 degree/s). Muscle contractile quality was derived by dividing the peak muscle torque with the respective LMM (lower limb muscle mass). Fasting blood glucose (FBG) and insulin were used to derive insulin resistance (HOMA-IR). Results: The control group was on average 10 years younger than the other two groups (p < 0.01). The LMM was similar across the three study groups. However, the age-adjusted mean muscle torque was significantly lower in both absolute and normalized isometric and isokinetic strength in PD and T2D groups compared to controls (p ? 0.01), with the difference persisting even after adjusting for age and other covariates. However, there was no difference in muscle strength and contractile quality between the PD and T2D study groups. Conclusions: Muscle strength and contractile quality would appear to be sensitive and early indices of the trajectory toward diabetes in Asian Indians and more so than skeletal muscle mass. It is thus important to recognize the importance of functional measurements among this population when considering the role of muscle in diabetes. The data also would suggest that specific muscle conditioning (e.g., resistance training) might have efficacy in improving function as well as muscle mass, and thus aiding in the prevention of the trajectory toward the development of T2D.
| S-EPMC6892303 | biostudies-literature
Project description:Insulin resistance is associated with mitochondrial dysfunction, but the mechanism by which mitochondria inhibit insulin-stimulated glucose uptake into the cytoplasm is unclear. The mitochondrial permeability transition pore (mPTP) is a protein complex that facilitates the exchange of molecules between the mitochondrial matrix and cytoplasm, and opening of the mPTP occurs in response to physiological stressors that are associated with insulin resistance. In this study, we investigated whether mPTP opening provides a link between mitochondrial dysfunction and insulin resistance by inhibiting the mPTP gatekeeper protein cyclophilin D (CypD) in vivo and in vitro. Mice lacking CypD were protected from high fat diet-induced glucose intolerance due to increased glucose uptake in skeletal muscle. The mitochondria in CypD knockout muscle were resistant to diet-induced swelling and had improved calcium retention capacity compared to controls; however, no changes were observed in muscle oxidative damage, insulin signaling, lipotoxic lipid accumulation or mitochondrial bioenergetics. In vitro, we tested 4 models of insulin resistance that are linked to mitochondrial dysfunction in cultured skeletal muscle cells including antimycin A, C2-ceramide, ferutinin, and palmitate. In all models, we observed that pharmacological inhibition of mPTP opening with the CypD inhibitor cyclosporin A was sufficient to prevent insulin resistance at the level of insulin-stimulated GLUT4 translocation to the plasma membrane. The protective effects of mPTP inhibition on insulin sensitivity were associated with improved mitochondrial calcium retention capacity but did not involve changes in insulin signaling both in vitro and in vivo. In sum, these data place the mPTP at a critical intersection between alterations in mitochondrial function and insulin resistance in skeletal muscle.
| S-EPMC3953683 | biostudies-literature
Project description:Skeletal muscle mitochondrial dysfunction occurs in many conditions including aging and insulin resistance, but the molecular pathways of the mitochondrial dysfunction remain unclear. Presently, no methodologies are available to measure synthesis rates of individual mitochondrial proteins, which limits our ability to fully understand the translational regulation of gene transcripts. Here, we report a methodology to measure synthesis rates of multiple muscle mitochondrial proteins, which, along with large-scale measurements of mitochondrial gene transcripts and protein concentrations, will enable us to determine whether mitochondrial alteration is due to transcriptional or translational changes. The methodology involves in vivo labeling of muscle proteins with l-[ring-(13)C(6)]phenylalanine, protein purification by two-dimensional gel electrophoresis of muscle mitochondrial fraction, and protein identification and stable isotope abundance measurements by tandem mass spectrometry. Synthesis rates of 68 mitochondrial and 23 nonmitochondrial proteins from skeletal muscle mitochondrial fraction showed a 10-fold range, with the lowest rate for a structural protein such as myosin heavy chain (0.16 +/- 0.04%/h) and the highest for a mitochondrial protein such as dihydrolipoamide branched chain transacylase E2 (1.5 +/- 0.42%/h). This method offers an opportunity to better define the translational regulation of proteins in skeletal muscle or other tissues.
| S-EPMC2584812 | biostudies-literature
Project description:Mitochondrial dysfunction has been implicated in the pathogenesis of type 2 diabetes, but its contribution to the early stages of dysglycemia remains poorly understood. By collecting a high-resolution stage-based spectrum of dysglycemia, our study fills this gap by evaluating derangement in both the function and quantity of mitochondria. We sampled mitochondria in skeletal muscle and subcutaneous adipose tissues of subjects with progressive advancement of dysglycemia under a three-month exercise intervention. We measured clinical metabolic parameters and gathered skeletal muscle and adipose tissue biopsies before and after the three-month exercise intervention. We then assayed the number of mitochondria via citrate synthase (CS) activity and functional parameters with high-resolution respirometry. In muscle, there were no differences in mitochondrial quantity or function at baseline between normoglycemics and prediabetics. However, the intervention caused improvement in CS activity, implying an increase in mitochondrial quantity. By contrast in adipose tissue, baseline differences in CS activity were present, with the lowest CS activity coincident with impaired fasting glucose and impaired glucose tolerance (IFG + IGT). Finally, CS activity, but few of the functional metrics, improved under the intervention. We show that in prediabetes, no differences in the function or amount of mitochondria (measured by CS activity) in skeletal muscle are apparent, but in adipose tissue of subjects with IFG + IGT, a significantly reduced activity of CS was observed. Finally, metabolic improvements under the exercise correlate to improvements in the amount, rather than function, of mitochondria in both tissues.
| S-EPMC8616473 | biostudies-literature
Project description:Skeletal muscle mitochondrial dysfunction is secondary to T2DM and can be improved by long-term regular exercise training Mitochondrial dysfunction has long been implicated to play a causative role in development of type 2 diabetes (T2DM). However, a growing number of recent studies provide data that mitochondrial dysfunction is a consequence of T2DM development. The aim of our study is to clarify in further detail the causal role of mitochondrial dysfunction in T2DM by a comprehensive ex vivo analysis of mitochondrial function combined with global gene expression analysis in muscle of pre-diabetic newly diagnosed untreated T2DM subjects and long-standing insulin treated T2DM subjects compared with age- and BMI-matched controls. In addition, we assessed the impact of long-term interval exercise training on physical activity performance, mitochondrial function and glycemic control in long-standing insulin-treated T2DM subjects. Ex vivo mitochondrial density, quality and functioning was comparable between pre-diabetic subjects and matched controls, however, gene expression analysis showed a switch from carbohydrate toward lipids as energy source in pre-diabetes subjects. In contrast, long-term insulin treated T2DM subjects had slightly decreased mitochondrial density and ex vivo function. Expression of Krebs cycle and OXPHOS related genes were decreased, indicating a decreased capacity to use lipids as an energy source. The insulin-treated T2DM subjects had a lower physical activity level than pre-diabetic and normoglycemic subjects. A 52 weeks exercise training of these subjects increased submaximal oxidative efficiency, increased in vivo PCr recovery rate, as well as mildly increased in vitro mitochondrial function. Gene expression of β-oxidation, Krebs cycle and OXPHOS-related genes was increased. Our data demonstrate that mitochondrial dysfunction is rather a consequence than a causative factor in T2DM development as it was only detected in overt diabetes and not in early diabetes. Regular exercise training stabilized exogenous insulin requirement and improved mitochondrial functioning, fatty acid oxidation and general physical work load capacity in long-standing insulin-treated T2DM subjects. As such, the present study shows for the first time that long-term exercise interventions are beneficial in this group of complex diabetes patient and may prevent further metabolic deterioration. Insulin-treated T2DM subjects before and after 52 weeks of exercise training (T2DM_0 and T2DM_52), normoglycemic controls (NGT) and pre-diabetes subjects (IGT) and were selected. RNA was extracted from skeletal muscle biopsies and hybridized on Affymetrix microarrays.
2010-11-29 | E-GEOD-19420 | biostudies-arrayexpress
Project description:AIMS/HYPOTHESIS: Insulin resistance and type 2 diabetes are associated with mitochondrial dysfunction. The aim of the present study was to test the hypothesis that oxidative phosphorylation and electron transport capacity are diminished in the skeletal muscle of type 2 diabetic subjects, as a result of a reduction in the mitochondrial content. MATERIALS AND METHODS: The O(2) flux capacity of permeabilised muscle fibres from biopsies of the quadriceps in healthy subjects (n = 8; age 58 +/- 2 years [mean+/-SEM]; BMI 28 +/- 1 kg/m(2); fasting plasma glucose 5.4 +/- 0.2 mmol/l) and patients with type 2 diabetes (n = 11; age 62 +/- 2 years; BMI 32 +/- 2 kg/m(2); fasting plasma glucose 9.0 +/- 0.8 mmol/l) was measured by high-resolution respirometry. RESULTS: O(2) flux expressed per mg of muscle (fresh weight) during ADP-stimulated state 3 respiration was lower (p < 0.05) in patients with type 2 diabetes in the presence of complex I substrate (glutamate) (31 +/- 2 vs 43 +/- 3 pmol O(2) s(-1) mg(-1)) and in response to glutamate + succinate (parallel electron input from complexes I and II) (63 +/- 3 vs 85 +/- 6 pmol s(-1) mg(-1)). Further increases in O(2) flux capacity were observed in response to uncoupling by FCCP, but were again lower (p < 0.05) in type 2 diabetic patients than in healthy control subjects (86 +/- 4 vs 109 +/- 8 pmol s(-1) mg(-1)). However, when O(2) flux was normalised for mitochondrial DNA content or citrate synthase activity, there were no differences in oxidative phosphorylation or electron transport capacity between patients with type 2 diabetes and healthy control subjects. CONCLUSIONS/INTERPRETATION: Mitochondrial function is normal in type 2 diabetes. Blunting of coupled and uncoupled respiration in type 2 diabetic patients can be attributed to lower mitochondrial content.
| S-EPMC1820754 | biostudies-other
Project description:Sialidases remove terminal sialic acids residues from the non-reducing ends of glycoconjugates. They have been recognized as catabolic enzymes that work within different subcellular compartments and can ensure the proper turn-over of glycoconjugates. Four mammalian sialidases (NEU1-4) exist, with different subcellular localization, pH optimum and substrate specificity. In zebrafish, seven different sialidases, with high homology to mammalian counterparts, have been identified. Zebrafish Neu3.2 is similar to the human cytosolic sialidase NEU2, which is involved in skeletal muscle differentiation and exhibits a broad substrate specificity toward gangliosides and glycoproteins. In zebrafish neu3.2, mRNA is expressed during somite development, and its enzymatic activity has been detected in the skeletal muscle and heart of adult animals. In this paper, 1-4-cell-stage embryos injected with neu3.2 splice-blocking morpholino showed severe embryonic defects, mainly in somites, heart and anterior-posterior axis formation. Myog and myod1 expressions were altered in morphants, and impaired musculature formation was associated with a defective locomotor behavior. Finally, the co-injection of Neu2 mouse mRNA in morphants rescued the phenotype. These data are consistent with the involvement of cytosolic sialidase in pathologies related to muscle formation and support the validity of the model to investigate the pathogenesis of the diseases.
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