Citations

BACKGROUND. Dementia is a rapidly expanding public health problem with major socio-economic burden. Insulin resistance (IR) is a prevalent but modifiable risk factor for dementia, yet its effects on brain structure, functional connectivity, and metabolism remain incompletely understood. METHODS. Regional brain glucose uptake (PET), volumes (MRI), functional connectivity (fMRI), and cognition (NIH Toolbox) was measured in 72 adults with or without markers of IR. To evaluate reversibility of IR-associated brain deficits, forty older adults with IR were randomized to forty weeks of metformin or placebo, and brain measures were repeated. As a proof-of-concept experiment, we developed a conditional brain-specific insulin receptor knockout mouse and assessed brain mitochondrial function and cognition. RESULTS. In older adults with markers of IR is associated with diminished total and regional brain volumes in areas critical for neuronal connectivity, memory, and learning, including cerebral white matter and the hippocampus. Reduced functional connectivity between brain regions detrimental for cognition was also noted. Further, we demonstrated that ATP production, essential for neuronal connectivity, was diminished in neuron-specific insulin receptor knockout mice accompanied by deficits in hippocampal- and prefrontal-dependent tasks. Forty weeks of metformin improved systemic insulin sensitivity concurrent to preserved brain glucose uptake, volume, and functional connectivity within specific regions central to decision-making and learning. Metformin was also associated with an improved composite measure of processing speed and working memory. CONCLUSION. These findings highlight IR as a key regulator of brain metabolism and support the concept that insulin sensitization can prevent neurobiological deficits in older people with IR.

ABSTRACT Early-life nutrition profoundly influences long-term metabolic health, and breast milk not only provides nutrients but also conveys maternal signals shaping infant metabolic development. While postpartum exercise by lactating women benefits maternal health, its impact on milk-borne signaling remains largely undefined. Small extracellular vesicles (sEVs) in breast milk are key mediators of maternal–infant communication because of their selectively packaged bioactive cargo and resistance to infant digestive enzymes and acids, enabling delivery of their cargo to peripheral tissues. Here, we show that a single session of moderate-intensity postpartum aerobic exercise robustly increases human breast milk sEV concentration, which persists for multiple post-exercise milk collections. Exercise enriches breast milk with sEVs containing regulatory metabolic cargo (proteins, miRNAs, and metabolites), which translates into enhanced mitochondrial capacity in neonatal-stage cells. These findings implicate sEVs as an exercise-responsive signaling compartment in breast milk capable of connecting postpartum maternal physical activity to beneficial infant metabolic programming. Highlights Acute moderate-intensity exercise increases human breast milk sEV concentration The exercise-mediated sEV increase lasts for multiple subsequent milk expressions Exercise coordinates a multi-omic enrichment of sEVs in breast milk Exercised breast milk sEVs enhance mitochondrial respiration in UC-MSCs

Abstract Insulin resistance (IR) is a modifiable risk factor for dementia, yet its effects on brain metabolism and function remain unclear. In older adults, greater IR was associated with reduced cerebral glucose uptake (indicating impaired mitochondrial metabolism), atrophy, and weakened connectivity between brain regions critical for cognition. In neuron-specific insulin receptor knockout mice, brain IR produced deficits in hippocampal- and prefrontal-dependent tasks accompanied by reduced brain mitochondrial ATP and elevated reactive oxygen species. To evaluate reversibility of IR-induced brain deficits, forty older adults with IR were randomized to 40-weeks of metformin or placebo. Metformin improved insulin sensitivity, increased brain glucose uptake, strengthened cognitive network connectivity, and preserved whole-brain and regional volumes implicated in decision-making and learning. Metformin also improved processing speed and working memory. Collectively, these findings highlight IR as a driver of brain metabolism and support the concept that insulin sensitization can prevent neurobiological deficits in older people with IR.

There is evidence that the anabolic response to exercise is blunted in skeletal muscle in older adults. Older adults also exhibit reduced mitochondrial content and lower oxidative capacity. Since mitochondria provide chemical energy for muscle protein synthesis, it is possible that age‐related changes to mitochondrial physiology may contribute to anabolic resistance. We evaluated this possibility by measuring mitochondrial function and anabolic responses to exercise in 12 young (19–34 yrs) and 12 older (67–83 yrs) adults. Serial vastus lateralis biopsies were collected during an infusion of 13 C 6 phenylalanine to measure muscle protein synthesis at baseline and 16 hours after a single bout of unaccustomed resistance exercise (unilateral knee extension, 8 sets, 10 repetitions at 70% of 1‐repetition maximum). Real‐time PCR and RNA sequencing were used to evaluate the transcriptional response to acute exercise in muscle tissue. Respiratory capacity of isolated mitochondria was measured by high‐resolution respirometry. Mitochondrial respiratory capacity was significantly lower in older adults (4.67±0.47 pmol/s/ug) compared to young (6.60±0.70 pmol/s/ug, p=0.024). Postabsorptive protein synthesis rates were similar in young and old for mixed muscle (Y: 0.067±0.005 %/hr, O: 0.104±0.030 %/hr, p=0.13), mitochondrial (Y: 0.076±0.014 %/hr, O: 0.089±0.017 %/hr, p=0.58), and myofibrillar fractions (Y: 0.073±0.005 %/hr, O: 0.072±0.015 %/hr, p=0.94). Exercise increased protein synthesis similarly in young and old for mixed muscle (Fold changes Y: 1.45±0.16, O: 1.46±0.18, p=0.98), mitochondrial (Y: 0.90±0.28, O: 1.74±0.41, p=0.11), and myofibrillar (Y: 1.35±0.13, O: 1.37±0.18, p=0.93). These data demonstrate older adults have lower mitochondrial respiratory capacity yet exhibit similar anabolic responses to resistance exercise compared to young. Protein synthesis does not appear limited by the decreased mitochondrial capacity with age.

We investigated the link between enhancement of SI (by hyperinsulinemic–euglycemic clamp) and muscle metabolites after 12 weeks of aerobic (high-intensity interval training [HIIT]), resistance training (RT), or combined training (CT) exercise in 52 lean healthy individuals. Muscle RNA sequencing revealed a significant association between SI after both HIIT and RT and the branched-chain amino acid (BCAA) metabolic pathway. Concurrently with increased expression and activity of branched-chain ketoacid dehydrogenase enzyme, many muscle amino metabolites, including BCAAs, glutamate, phenylalanine, aspartate, asparagine, methionine, and γ-aminobutyric acid, increased with HIIT, supporting the substantial impact of HIIT on amino acid metabolism. Short-chain C3 and C5 acylcarnitines were reduced in muscle with all three training modes, but unlike RT, both HIIT and CT increased tricarboxylic acid metabolites and cardiolipins, supporting greater mitochondrial activity with aerobic training. Conversely, RT and CT increased more plasma membrane phospholipids than HIIT, suggesting a resistance exercise effect on cellular membrane protection against environmental damage. Sex and age contributed modestly to the exercise-induced changes in metabolites and their association with cardiometabolic parameters. Integrated transcriptomic and metabolomic analyses suggest various clusters of genes and metabolites are involved in distinct effects of HIIT, RT, and CT. These distinct metabolic signatures of different exercise modes independently link each type of exercise training to improved SI and cardiometabolic risk. Article Highlights We aimed to understand the link between skeletal muscle metabolites and cardiometabolic health after exercise training. Although aerobic, resistance, and combined exercise training each enhance muscle insulin sensitivity as well as other cardiometabolic parameters, they disparately alter amino and citric acid metabolites as well as the lipidome, linking these metabolomic changes independently to the improvement of cardiometabolic risks with each exercise training mode. These findings reveal an important layer of the unique exercise mode–dependent changes in muscle metabolism, which may eventually lead to more informed exercise prescription for improving SI.

We assessed the effects of 12 wk of supervised high-intensity interval training (HIIT), resistance training, and combined training (CT) on skeletal muscle mitochondrial abundance and markers of fission and fusion. HIIT increased mitochondrial area and size and promoted protein changes indicative of increased mitochondrial fusion, whereas lessor effects were observed after CT and no changes were observed after RT. Furthermore, increased mitochondrial area and size after HIIT associated with improved mitochondrial respiration, cardiorespiratory fitness, and insulin sensitivity.

Transient insulin deprivation with concurrent hyperglucagonemia is a catabolic state that can occur in type 1 diabetes. To evaluate glucagon’s catabolic effect in the setting of its glucogenic effect, we measured the regional exchanges of amino acid metabolites (amino-metabolites) across muscle and splanchnic beds in 16 healthy humans during either somatostatin followed by glucagon or saline infusion alone. Despite a twofold or greater increase in the regional exchange of amino-metabolites by glucagon, whole-body kinetics and concentrations of amino acids (AA) remained stable. Glucagon increased the splanchnic uptake of not only gluconeogenic but also essential (EAA) AA while increasing their release from the muscle bed. Regional tracer-based kinetics and 3-methylhistidine release indicate that EAA release from muscle is likely caused by reduced protein synthesis rather than increased protein degradation. Furthermore, many metabolites known to affect insulin action and metabolism were altered by hyperglucagonemia including increase in branched-chain AA and keto acids of leucine and isoleucine in arterial plasma. Further, an increase in arterial concentrations of α-aminoadipic acid arising from increased conversion from lysine in the splanchnic bed was noted. These results demonstrate that hyperglucagonemia during hypoinsulinemia increases net muscle protein catabolism and substantially increases the exchange of amino metabolites across splanchnic and muscle beds.

Abstract Context Familial partial lipodystrophy (FPL), Dunnigan variety is characterized by skeletal muscle hypertrophy and insulin resistance besides fat loss from the extremities. The cause for the muscle hypertrophy and its functional consequences is not known. Objective To compare muscle strength and endurance, besides muscle protein synthesis rate between subjects with FPL and matched controls (n = 6 in each group). In addition, we studied skeletal muscle mitochondrial function and gene expression pattern to help understand the mechanisms for the observed differences. Methods Body composition by dual-energy X-ray absorptiometry, insulin sensitivity by minimal modelling, assessment of peak muscle strength and fatigue, skeletal muscle biopsy and calculation of muscle protein synthesis rate, mitochondrial respirometry, skeletal muscle transcriptome, proteome, and gene set enrichment analysis. Results Despite increased muscularity, FPL subjects did not demonstrate increased muscle strength but had earlier fatigue on chest press exercise. Decreased mitochondrial state 3 respiration in the presence of fatty acid substrate was noted, concurrent to elevated muscle lactate and decreased long-chain acylcarnitine. Based on gene transcriptome, there was significant downregulation of many critical metabolic pathways involved in mitochondrial biogenesis and function. Moreover, the overall pattern of gene expression was indicative of accelerated aging in FPL subjects. A lower muscle protein synthesis and downregulation of gene transcripts involved in muscle protein catabolism was observed. Conclusion Increased muscularity in FPL is not due to increased muscle protein synthesis and is likely due to reduced muscle protein degradation. Impaired mitochondrial function and altered gene expression likely explain the metabolic abnormalities and skeletal muscle dysfunction in FPL subjects.