Cystine/glutamate antiporter xCT controls skeletal muscle glutathione redox, bioenergetics and differentiation.

Cysteine, the rate-controlling amino acid in cellular glutathione synthesis is imported as cystine, by the cystine/glutamate antiporter, xCT, and subsequently reduced to cysteine. As glutathione redox is important in muscle regeneration in aging, we hypothesized that xCT exerts upstream control over skeletal muscle glutathione redox, metabolism and regeneration. Bioinformatic analyses of publicly available datasets revealed that expression levels of xCT and GSH-related genes are inversely correlated with myogenic differentiation genes. Muscle satellite cells (MuSCs) isolated from Slc7a11sut/sut mice, which harbour a mutation in the Slc7a11 gene encoding xCT, required media supplementation with 2-mercaptoethanol to support cell proliferation but not myotube differentiation, despite persistently lower GSH. Slc7a11sut/sut primary myotubes were larger compared to WT myotubes, and also exhibited higher glucose uptake and cellular oxidative capacities. Immunostaining of myogenic markers (Pax7, MyoD, and myogenin) in cardiotoxin-damaged tibialis anterior muscle fibres revealed greater MuSC activation and commitment to differentiation in Slc7a11sut/sut muscle compared to WT mice, culminating in larger myofiber cross-sectional areas at 21 days post-injury. Slc7a11sut/sut mice subjected to a 5-week exercise training protocol demonstrated enhanced insulin tolerance compared to WT mice, but blunted muscle mitochondrial biogenesis and respiration in response to exercise training. Our results demonstrate that the absence of xCT inhibits cell proliferation but promotes myotube differentiation by regulating cellular metabolism and glutathione redox. Altogether, these results support the notion that myogenesis is a redox-regulated process and may help inform novel therapeutic approaches for muscle wasting and dysfunction in aging and disease.

Accessory subunit NDUFB4 participates in mitochondrial complex I supercomplex formation.

Mitochondrial electron transport chain complexes organize into supramolecular structures called respiratory supercomplexes (SCs). The role of respiratory SCs remains largely unconfirmed despite evidence supporting their necessity for mitochondrial respiratory function. The mechanisms underlying the formation of the I1III2IV1 "respirasome" SC are also not fully understood, further limiting insights into these processes in physiology and diseases, including neurodegeneration and metabolic syndromes. NDUFB4 is a complex I accessory subunit that contains residues that interact with the subunit UQCRC1 from complex III, suggesting that NDUFB4 is integral for I1III2IV1 respirasome integrity. Here, we introduced specific point mutations to Asn24 (N24) and Arg30 (R30) residues on NDUFB4 to decipher the role of I1III2-containing respiratory SCs in cellular metabolism while minimizing the functional consequences to complex I assembly. Our results demonstrate that NDUFB4 point mutations N24A and R30A impair I1III2IV1 respirasome assembly and reduce mitochondrial respiratory flux. Steady-state metabolomics also revealed a global decrease in citric acid cycle metabolites, affecting NADH-generating substrates. Taken together, our findings highlight an integral role of NDUFB4 in respirasome assembly and demonstrate the functional significance of SCs in regulating mammalian cell bioenergetics.

The SARS-CoV-2 spike glycoprotein interacts with MAO-B and impairs mitochondrial energetics.

SARS-CoV-2 infection is associated with both acute and post-acute neurological symptoms. Emerging evidence suggests that SARS-CoV-2 can alter mitochondrial metabolism, suggesting that changes in brain metabolism may contribute to the development of acute and post-acute neurological complications. Monoamine oxidase B (MAO-B) is a flavoenzyme located on the outer mitochondrial membrane that catalyzes the oxidative deamination of monoamine neurotransmitters. Computational analyses have revealed high similarity between the SARS-CoV-2 spike glycoprotein receptor binding domain on the ACE2 receptor and MAO-B, leading to the hypothesis that SARS-CoV-2 spike glycoprotein may alter neurotransmitter metabolism by interacting with MAO-B. Our results empirically establish that the SARS-CoV-2 spike glycoprotein interacts with MAO-B, leading to increased MAO-B activity in SH-SY5Y neuron-like cells. Common to neurodegenerative disease pathophysiological mechanisms, we also demonstrate that the spike glycoprotein impairs mitochondrial bioenergetics, induces oxidative stress, and perturbs the degradation of depolarized aberrant mitochondria through mitophagy. Our findings also demonstrate that SH-SY5Y neuron-like cells expressing the SARS-CoV-2 spike protein were more susceptible to MPTP-induced necrosis, likely necroptosis. Together, these results reveal novel mechanisms that may contribute to SARS-CoV-2-induced neurodegeneration.

GDF15 promotes weight loss by enhancing energy expenditure in muscle.

Caloric restriction that promotes weight loss is an effective strategy for treating non-alcoholic fatty liver disease and improving insulin sensitivity in people with type 2 diabetes1. Despite its effectiveness, in most individuals, weight loss is usually not maintained partly due to physiological adaptations that suppress energy expenditure, a process known as adaptive thermogenesis, the mechanistic underpinnings of which are unclear2,3. Treatment of rodents fed a high-fat diet with recombinant growth differentiating factor 15 (GDF15) reduces obesity and improves glycaemic control through glial-cell-derived neurotrophic factor family receptor α-like (GFRAL)-dependent suppression of food intake4-7. Here we find that, in addition to suppressing appetite, GDF15 counteracts compensatory reductions in energy expenditure, eliciting greater weight loss and reductions in non-alcoholic fatty liver disease (NAFLD) compared to caloric restriction alone. This effect of GDF15 to maintain energy expenditure during calorie restriction requires a GFRAL-ß-adrenergic-dependent signalling axis that increases fatty acid oxidation and calcium futile cycling in the skeletal muscle of mice. These data indicate that therapeutic targeting of the GDF15-GFRAL pathway may be useful for maintaining energy expenditure in skeletal muscle during caloric restriction.

Novel Homozygous Variant in COQ7 in Siblings With Hereditary Motor Neuropathy.

Background and Objectives: Coenzyme Q10 (CoQ10) is an important electron carrier and antioxidant. The COQ7 enzyme catalyzes the hydroxylation of 5-demethoxyubiquinone-10 (DMQ10), the second-to-last step in the CoQ10 biosynthesis pathway. We report a consanguineous family presenting with a hereditary motor neuropathy associated with a homozygous c.1A > G p.? variant of COQ7 with abnormal CoQ10 biosynthesis. Methods: Affected family members underwent clinical assessments that included nerve conduction testing, histologic analysis, and MRI. Pathogenicity of the COQ7 variant was assessed in cultured fibroblasts and skeletal muscle using a combination of immunoblots, respirometry, and quinone analysis. Results: Three affected siblings, ranging from 12 to 24 years of age, presented with a severe length-dependent motor neuropathy with marked symmetric distal weakness and atrophy with normal sensation. Muscle biopsy of the quadriceps revealed chronic denervation pattern. An MRI examination identified moderate to severe fat infiltration in distal muscles. Exome sequencing demonstrated the homozygous COQ7 c.1A > G p.? variant that is expected to bypass the first 38 amino acid residues at the n-terminus, initiating instead with methionine at position 39. This is predicted to cause the loss of the cleavable mitochondrial targeting sequence and 2 additional amino acids, thereby preventing the incorporation and subsequent folding of COQ7 into the inner mitochondrial membrane. Pathogenicity of the COQ7 variant was demonstrated by diminished COQ7 and CoQ10 levels in muscle and fibroblast samples of affected siblings but not in the father, unaffected sibling, or unrelated controls. In addition, fibroblasts from affected siblings had substantial accumulation of DMQ10, and maximal mitochondrial respiration was impaired in both fibroblasts and muscle. Discussion: This report describes a new neurologic phenotype of COQ7-related primary CoQ10 deficiency. Novel aspects of the phenotype presented by this family include pure distal motor neuropathy involvement, as well as the lack of upper motor neuron features, cognitive delay, or sensory involvement in comparison with cases of COQ7-related CoQ10 deficiency previously reported in the literature.

Minimal adaptation of the molecular regulators of mitochondrial dynamics in response to unilateral limb immobilisation and retraining in middle-aged men.

PURPOSE: Mitochondrial dynamics are regulated by the differing molecular pathways variously governing biogenesis, fission, fusion, and mitophagy. Adaptations in mitochondrial morphology are central in driving the improvements in mitochondrial bioenergetics following exercise training. However, there is a limited understanding of mitochondrial dynamics in response to inactivity. METHODS: Skeletal muscle biopsies were obtained from middle-aged males (n = 24, 49.4 ± 3.2 years) who underwent sequential 14-day interventions of unilateral leg immobilisation, ambulatory recovery, and resistance training. We quantified vastus lateralis gene and protein expression of key proteins involved in mitochondrial biogenesis, fusion, fission, and turnover in at baseline and following each intervention. RESULTS: PGC1α mRNA decreased 40% following the immobilisation period, and was accompanied by a 56% reduction in MTFP1 mRNA, a factor involved in mitochondrial fission. Subtle mRNA decreases were also observed in TFAM (17%), DRP1 (15%), with contrasting increases in BNIP3L and PRKN following immobilisation. These changes in gene expression were not accompanied by changes in respective protein expression. Instead, we observed subtle decreases in NRF1 and MFN1 protein expression. Ambulatory recovery restored mRNA and protein expression to pre-intervention levels of all altered components, except for BNIP3L. Resistance training restored BNIP3L mRNA to pre-intervention levels, and further increased mRNA expression of OPA-1, MFN2, MTFP1, and PINK1 past baseline levels. CONCLUSION: In healthy middle-aged males, 2 weeks of immobilisation did not induce dramatic differences in markers of mitochondria fission and autophagy. Restoration of ambulatory physical activity following the immobilisation period restored altered gene expression patterns to pre-intervention levels, with little evidence of further adaptation to resistance exercise training.

Exercise training enhances muscle mitochondrial metabolism in diet-resistant obesity.

BACKGROUND: Current paradigms for predicting weight loss in response to energy restriction have general validity but a subset of individuals fail to respond adequately despite documented diet adherence. Patients in the bottom 20% for rate of weight loss following a hypocaloric diet (diet-resistant) have been found to have less type I muscle fibres and lower skeletal muscle mitochondrial function, leading to the hypothesis that physical exercise may be an effective treatment when diet alone is inadequate. In this study, we aimed to assess the efficacy of exercise training on mitochondrial function in women with obesity with a documented history of minimal diet-induced weight loss. METHODS: From over 5000 patient records, 228 files were reviewed to identify baseline characteristics of weight loss response from women with obesity who were previously classified in the top or bottom 20% quintiles based on rate of weight loss in the first 6 weeks during which a 900 kcal/day meal replacement was consumed. A subset of 20 women with obesity were identified based on diet-resistance (n=10) and diet sensitivity (n=10) to undergo a 6-week supervised, progressive, combined aerobic and resistance exercise intervention. FINDINGS: Diet-sensitive women had lower baseline adiposity, higher fasting insulin and triglycerides, and a greater number of ATP-III criteria for metabolic syndrome. Conversely in diet-resistant women, the exercise intervention improved body composition, skeletal muscle mitochondrial content and metabolism, with minimal effects in diet-sensitive women. In-depth analyses of muscle metabolomes revealed distinct group- and intervention- differences, including lower serine-associated sphingolipid synthesis in diet-resistant women following exercise training. INTERPRETATION: Exercise preferentially enhances skeletal muscle metabolism and improves body composition in women with a history of minimal diet-induced weight loss. These clinical and metabolic mechanism insights move the field towards better personalised approaches for the treatment of distinct obesity phenotypes. FUNDING: Canadian Institutes of Health Research (CIHR-INMD and FDN-143278; CAN-163902; CIHR PJT-148634).

Targeting skeletal muscle mitochondrial health in obesity.

Metabolic demands of skeletal muscle are substantial and are characterized normally as highly flexible and with a large dynamic range. Skeletal muscle composition (e.g., fiber type and mitochondrial content) and metabolism (e.g., capacity to switch between fatty acid and glucose substrates) are altered in obesity, with some changes proceeding and some following the development of the disease. Nonetheless, there are marked interindividual differences in skeletal muscle composition and metabolism in obesity, some of which have been associated with obesity risk and weight loss capacity. In this review, we discuss related molecular mechanisms and how current and novel treatment strategies may enhance weight loss capacity, particularly in diet-resistant obesity.

Grx2 Regulates Skeletal Muscle Mitochondrial Structure and Autophagy.

Glutathione is an important antioxidant that regulates cellular redox status and is disordered in many disease states. Glutaredoxin 2 (Grx2) is a glutathione-dependent oxidoreductase that plays a pivotal role in redox control by catalyzing reversible protein deglutathionylation. As oxidized glutathione (GSSG) can stimulate mitochondrial fusion, we hypothesized that Grx2 may contribute to the maintenance of mitochondrial dynamics and ultrastructure. Here, we demonstrate that Grx2 deletion results in decreased GSH:GSSG, with a marked increase of GSSG in primary muscle cells isolated from C57BL/6 Grx2-/- mice. The altered glutathione redox was accompanied by increased mitochondrial length, consistent with a more fused mitochondrial reticulum. Electron microscopy of Grx2-/- skeletal muscle fibers revealed decreased mitochondrial surface area, profoundly disordered ultrastructure, and the appearance of multi-lamellar structures. Immunoblot analysis revealed that autophagic flux was augmented in Grx2-/- muscle as demonstrated by an increase in the ratio of LC3II/I expression. These molecular changes resulted in impaired complex I respiration and complex IV activity, a smaller diameter of tibialis anterior muscle, and decreased body weight in Grx2 deficient mice. Together, these are the first results to show that Grx2 regulates skeletal muscle mitochondrial structure, and autophagy.

Daily protein supplementation attenuates immobilization-induced blunting of postabsorptive muscle mTORC1 activation in middle-aged men.

Disuse-induced muscle atrophy is accompanied by a blunted postprandial response of the mammalian target of rapamycin complex 1 (mTORC1) pathway. Conflicting observations exist as to whether postabsorptive mTORC1 pathway activation is also blunted by disuse and plays a role in atrophy. It is unknown whether changes in habitual protein intake alter mTORC1 regulatory proteins and how they may contribute to the development of anabolic resistance. The primary objective of this study was to characterize the downstream responsiveness of skeletal muscle mTORC1 activation and its upstream regulatory factors, following 14 days of lower limb disuse in middle-aged men (45-60 yr). The participants were further randomized to receive daily supplementation of 20 g/d of protein (n = 12; milk protein concentrate) or isocaloric carbohydrate placebo (n = 13). Immobilization reduced postabsorptive skeletal muscle phosphorylation of the mTORC1 downstream targets, 4E-BP1, P70S6K, and ribosomal protein S6 (RPS6), with phosphorylation of the latter two decreasing to a greater extent in the placebo, compared with the protein supplementation groups (37% ± 13% vs. 14% ± 11% and 38% ± 20% vs. 25% ± 8%, respectively). Sestrin2 protein was also downregulated following immobilization irrespective of supplement group, despite a corresponding increase in its mRNA content. This decrease in Sestrin2 protein was negatively correlated with the immobilization-induced change in the in silico-predicted regulator miR-23b-3p. No other measured upstream proteins were altered by immobilization or supplementation. Immobilization downregulated postabsorptive mTORC1 pathway activation, and 20 g/day of protein supplementation attenuated the decrease in phosphorylation of targets regulating muscle protein synthesis.

The lifecycle of skeletal muscle mitochondria in obesity.

Skeletal muscle possesses dramatic metabolic plasticity that allows for the rapid adaptation in cellular energy transduction to meet the demands of the organism. Obesity elicits changes in skeletal muscle structure and function, resulting in the accumulation of intramuscular lipids. The accumulation of intramuscular lipids in obesity is associated with impaired skeletal muscle mitochondrial content and function. Mitochondria exist as a dynamic network that is regulated by the processes of biogenesis, fusion, fission, and mitophagy. In this review, we outline adaptations in molecular pathways that regulate mitochondrial structure and function in obesity. We highlight the emerging role of dysregulated skeletal muscle macroautophagy and mitochondrial turnover in obesity. Future research should further elucidate the role of mitophagy in observed reductions in mitochondrial content and function during obesity.

Comparison of the Acute Postprandial Circulating B-Vitamin and Vitamer Responses to Single Breakfast Meals in Young and Older Individuals: Preliminary Secondary Outcomes of a Randomized Controlled Trial.

B-vitamin deficiency is common in ageing populations either due to altered dietary habits or altered digestive and metabolic functions. There is limited data on the acute circulating concentrations of B-vitamins and their various forms (vitamers), following ingestion of realistic meals. This study compared the acute circulating B-vitamin and vitamer responses to either an energy-dense (ED) or a nutrient-dense (ND) breakfast meal, consumed in a randomized cross-over sequence, in older and younger adults (n = 15 and 15, aged 67.3 ± 1.5 and 22.7 ± 0.5 years (mean ± SEM), respectively). Eleven differing B-vitamins and vitamers were determined in plasma samples by ultra-high-performance liquid chromatography-tandem mass spectrometry, in the fasting and postprandial state (hourly for 5 h). While postprandial thiamine concentration increased following both meals, riboflavin increased only following a ND meal in both age groups. Many vitamins including nicotinic acid, pantothenic acid, pyridoxal, pyridoxamine, pyridoxal-5'phosphate, and 4-pyridoxic acid remained unaltered, and flavin mononucleotide (FMN), nicotinamide and nicotinuric acid concentrations reduced following both meals. Biological age and food composition had minimal impact on postprandial B-vitamin concentrations, yet the differences between the ED and ND meals for riboflavin highlight the importance of riboflavin intake to achieve adequacy.

Exercise recovery increases skeletal muscle H2O2 emission and mitochondrial respiratory capacity following two-weeks of limb immobilization.

Extended periods of skeletal muscle disuse result in muscle atrophy. Following limb immobilization, increased mitochondrial reactive oxygen species (ROS) production may contribute to atrophy through increases in skeletal muscle protein degradation. However, the effect of skeletal muscle disuse on mitochondrial ROS production remains unclear. This study investigated the effect of immobilization, followed by two subsequent periods of restored physical activity, on mitochondrial H2O2 emissions in adult male skeletal muscle. Middle-aged men (n = 30, 49.7 ±â€¯3.84 y) completed two weeks of unilateral lower-limb immobilization, followed by two weeks of baseline-matched activity, consisting of 10,000 steps a day, then completed two weeks of three times weekly supervised resistance training. Vastus lateralis biopsies were taken at baseline, post-immobilization, post-ambulatory recovery, and post-resistance-training. High-resolution respirometry was used simultaneously with fluorometry to determine mitochondrial respiration and hydrogen peroxide (H2O2) production in permeabilized muscle fibres. Mitochondrial H2O2 emission with complex I and II substrates, in the absence of ADP, was greater following immobilization, however, there was no effect on mitochondrial respiration. Both ambulatory recovery and resistance training, following the period of immobilization, increased in mitochondrial H2O2 emissions. These data demonstrated that 2 weeks of immobilization increases mitochondrial H2O2 emissions, but subsequent retraining periods of ambulatory recovery and resistance training also led to in robust increases in mitochondrial H2O2 emissions in skeletal muscle.

Impact of dairy protein during limb immobilization and recovery on muscle size and protein synthesis; a randomized controlled trial.

Muscle disuse results in the loss of muscular strength and size, due to an imbalance between protein synthesis (MPS) and breakdown (MPB). Protein ingestion stimulates MPS, although it is not established if protein is able to attenuate muscle loss with immobilization (IM) or influence the recovery consisting of ambulatory movement followed by resistance training (RT). Thirty men (49.9 ± 0.6 yr) underwent 14 days of unilateral leg IM, 14 days of ambulatory recovery (AR), and a further six RT sessions over 14 days. Participants were randomized to consume an additional 20 g of dairy protein or placebo with a meal during the intervention. Isometric knee extension strength was reduced following IM (-24.7 ± 2.7%), partially recovered with AR (-8.6 ± 2.6%), and fully recovered after RT (-0.6 ± 3.4%), with no effect of supplementation. Thigh muscle cross-sectional area decreased with IM (-4.1 ± 0.5%), partially recovered with AR (-2.1 ± 0.5%), and increased above baseline with RT (+2.2 ± 0.5%), with no treatment effect. Myofibrillar MPS, measured using deuterated water, was unaltered by IM, with no effect of protein. During AR, MPS was increased only with protein supplementation. Protein supplementation did not attenuate the loss of muscle size and function with disuse or potentiate recovery but enhanced myofibrillar MPS during AR. NEW & NOTEWORTHY Twenty grams of daily protein supplementation does not attenuate the loss of muscle size and function induced by 2 wk of muscle disuse or potentiate recovery in middle-age men. Average mitochondrial but not myofibrillar muscle protein synthesis was attenuated during immobilization with no effect of supplementation. Protein supplementation increased myofibrillar protein synthesis during a 2-wk period of ambulatory recovery following disuse but without group differences in phenotype recovery.

Comparisons of the Postprandial Inflammatory and Endotoxaemic Responses to Mixed Meals in Young and Older Individuals: A Randomised Trial.

Postprandial inflammation and endotoxaemia are determinants of cardiovascular and metabolic disease risk which are amplified by high fat meals. We aimed to examine the determinants of postprandial inflammation and endotoxaemia in older and younger adults following a high fat mixed meal. In a randomised cross-over trial, healthy participants aged 20-25 and 60-75 years (n = 15/group) consumed a high-fat breakfast and a low-fat breakfast. Plasma taken at baseline and post-meal for 5 h was analysed for circulating endotoxin, cytokines (monocyte chemotactic protein-1 (MCP-1), interleukin (IL)-1ß, IL-6, and tumour necrosis factor-alpha (TNF-α)), lipopolysaccharide binding protein (LBP), and inflammatory gene expression in peripheral blood mononuclear cells (PBMC). Older subjects had lower baseline PBMC expression of Glutathione peroxidase 1 (GPX-1) but greater insulin-like growth factor-binding protein 3 (IGFBP3) and circulating MCP-1 compared to younger subjects. After either meal, there were no age differences in plasma, chylomicron endotoxin, or plasma LBP concentrations, nor in inflammatory cytokine gene and protein expression (MCP-1, IL-1ß, and TNF-α). Unlike younger participants, the older group had decreased superoxide dismutase (SOD)-2 expression after the meals. After a high-fat meal, older adults have no increased inflammatory or endotoxin response, but an altered oxidative stress gene response compared with younger adults. Healthy older adults, without apparent metabolic dysfunction, have a comparable postprandial inflammatory and endotoxaemia response to younger adults.

Maternal High Fat Diet Alters Skeletal Muscle Mitochondrial Catalytic Activity in Adult Male Rat Offspring.

A maternal high-fat (HF) diet during pregnancy can lead to metabolic compromise, such as insulin resistance in adult offspring. Skeletal muscle mitochondrial dysfunction is one mechanism contributing to metabolic impairments in insulin resistant states. Therefore, the present study aimed to investigate whether mitochondrial dysfunction is evident in metabolically compromised offspring born to HF-fed dams. Sprague-Dawley dams were randomly assigned to receive a purified control diet (CD; 10% kcal from fat) or a high fat diet (HFD; 45% kcal from fat) for 10 days prior to mating, throughout pregnancy and during lactation. From weaning, all male offspring received a standard chow diet and soleus muscle was collected at day 150. Expression of the mitochondrial transcription factors nuclear respiratory factor-1 (NRF1) and mitochondrial transcription factor A (mtTFA) were downregulated in HF offspring. Furthermore, genes encoding the mitochondrial electron transport system (ETS) respiratory complex subunits were suppressed in HF offspring. Moreover, protein expression of the complex I subunit, NDUFB8, was downregulated in HF offspring (36%), which was paralleled by decreased maximal catalytic linked activity of complex I and III (40%). Together, these results indicate that exposure to a maternal HF diet during development may elicit lifelong mitochondrial alterations in offspring skeletal muscle.

Older adults have an altered chylomicron response to a high-fat meal.

Ageing is associated with a prolonged and exaggerated postprandial lipaemia. This study aimed to examine the contribution of alterations in chylomicron synthesis, size and lipid composition to increased lipaemia. Healthy older (60-75 years; n 15) and younger (20-25 years; n 15) subjects consumed a high-fat breakfast. Chylomicron dynamics and fatty acid composition were analysed for 5 h in the postprandial state. Plasma TAG levels were elevated following the meal in the older subjects, relative to younger subjects (P<0·01). For older subjects compared with younger subjects, circulating chylomicron particle size was smaller (P<0·05), with greater apoB content (P<0·05) at all postprandial time points. However, total chylomicron TAG concentration between the groups was unaltered post-meal. Compared with younger subjects, the older subjects exhibited a greater proportion of oleic acid in the TAG and phospholipid (PL) fraction (P<0·05), plus lower proportions of linoleic acid in the TAG fraction of the chylomicrons (P<0·01). Thus, following the ingestion of a high-fat meal, older individuals demonstrate both smaller, more numerous chylomicrons, with a greater total MUFA and lower PUFA contents. These data suggest that the increased postprandial lipaemia of ageing cannot be attributed to increased chylomicron TAG. Rather, ageing is associated with changes in chylomicron particle size, apoB content and fatty acid composition of the chylomicron TAG and PL fractions.

Impaired Ribosome Biogenesis and Skeletal Muscle Growth in a Murine Model of Inflammatory Bowel Disease.

BACKGROUND: Inflammation is a factor potentially underpinning skeletal muscle mass. Intestinal-derived inflammation in inflammatory bowel disease (IBD) results in loss of muscle mass; however, the underlying mechanism is unclear. The interleukin 10 gene-deficient (Il10-/-) mouse is a genetically modified animal model of IBD that can be used to study the effect of intestinal-derived inflammation on muscles. METHODS: Il10-/- and C57BL/6 wild-type (WT) mice were inoculated with intestinal bacteria to induce colon inflammation at the fifth week of age. Skeletal muscles were collected between 7 and 14 weeks of age for analysis of muscle weight, myofiber cross-sectional area (CSA), and molecular markers of inflammation and anabolism pathways, with a focus on ribosome biogenesis. RESULTS: Il10-/- animals that developed colon inflammation had a marked increase in muscle immunoglobulin G (IgG) compared with WT. Inflamed Il10-/- animals had impaired muscle mass gain and smaller myofiber CSA. Intramuscular IgG deposition negatively correlated with muscle mass. After the onset of muscle inflammation, Il10-/- mice had decreased levels of total and ribosomal RNAs (45S, 28S, 18S, and 5.8S rRNAs). Inflammation inversely correlated with muscle levels of total RNA and 28S rRNA which in turn positively correlated with muscle mass. The abundance of growth-related proteins (p70S6K and upstream binding factor, UBF) was decreased in Il10-/- mice. CONCLUSIONS: Muscle inflammation and associated decline of ribosome biogenesis lead to muscle growth impairment in Il10-/- mice. This may have implications for maintenance of muscle mass in conditions associated with chronic intestinal-derived inflammation.