Muscle-generated BDNF is a sexually dimorphic myokine that controls metabolic flexibility.
ABSTRACT: The ability of skeletal muscle to switch between lipid and glucose oxidation for ATP production during metabolic stress is pivotal for maintaining systemic energy homeostasis, and dysregulation of this metabolic flexibility is a dominant cause of several metabolic disorders. However, the molecular mechanism that governs fuel selection in muscle is not well understood. Here, we report that brain-derived neurotrophic factor (BDNF) is a fasting-induced myokine that controls metabolic reprograming through the AMPK/CREB/PGC-1? pathway in female mice. Female mice with a muscle-specific deficiency in BDNF (MBKO mice) were unable to switch the predominant fuel source from carbohydrates to fatty acids during fasting, which reduced ATP production in muscle. Fasting-induced muscle atrophy was also compromised in female MBKO mice, likely a result of autophagy inhibition. These mutant mice displayed myofiber necrosis, weaker muscle strength, reduced locomotion, and muscle-specific insulin resistance. Together, our results show that muscle-derived BDNF facilitates metabolic adaption during nutrient scarcity in a gender-specific manner and that insufficient BDNF production in skeletal muscle promotes the development of metabolic myopathies and insulin resistance.
Project description:Fasting and glucose shortage activate a metabolic switch that shifts more energy production to mitochondria. This metabolic adaptation ensures energy supply, but also elevates the risk of mitochondrial oxidative damage. Here, we present evidence that metabolically challenged mitochondria undergo active fusion to suppress oxidative stress. In response to glucose starvation, mitofusin 1 (MFN1) becomes associated with the protein deacetylase HDAC6. This interaction leads to MFN1 deacetylation and activation, promoting mitochondrial fusion. Deficiency in HDAC6 or MFN1 prevents mitochondrial fusion induced by glucose deprivation. Unexpectedly, failure to undergo fusion does not acutely affect mitochondrial adaptive energy production; instead, it causes excessive production of mitochondrial reactive oxygen species and oxidative damage, a defect suppressed by an acetylation-resistant MFN1 mutant. In mice subjected to fasting, skeletal muscle mitochondria undergo dramatic fusion. Remarkably, fasting-induced mitochondrial fusion is abrogated in HDAC6-knockout mice, resulting in extensive mitochondrial degeneration. These findings show that adaptive mitochondrial fusion protects metabolically challenged mitochondria.
Project description:Skeletal muscle plays important roles in whole-body glucose and fatty acid metabolism. However, muscle also secretes cytokines and growth factors (collectively termed myokines) that can potentially act in an autocrine, a paracrine, and/or an endocrine manner to modulate metabolic, inflammatory, and other processes. Here, we report the identification and characterization of myonectin, a novel myokine belonging to the C1q/TNF-related protein (CTRP) family. Myonectin transcript was highly induced in differentiated myotubes and predominantly expressed by skeletal muscle. Circulating levels of myonectin were tightly regulated by the metabolic state; fasting suppressed, but refeeding dramatically increased, its mRNA and serum levels. Although mRNA and circulating levels of myonectin were reduced in a diet-induced obese state, voluntary exercise increased its expression and circulating levels. Accordingly, myonectin transcript was up-regulated by compounds (forskolin, epinephrine, ionomycin) that raise cellular cAMP or calcium levels. In vitro, secreted myonectin forms disulfide-linked oligomers, and when co-expressed, forms heteromeric complexes with other members of the C1q/TNF-related protein family. In mice, recombinant myonectin administration reduced circulating levels of free fatty acids without altering adipose tissue lipolysis. Consistent with this, myonectin promoted fatty acid uptake in cultured adipocytes and hepatocytes, in part by up-regulating the expression of genes (CD36, FATP1, Fabp1, and Fabp4) that promote lipid uptake. Collectively, these results suggest that myonectin links skeletal muscle to lipid homeostasis in liver and adipose tissue in response to alterations in energy state, revealing a novel myonectin-mediated metabolic circuit.
Project description:Kidney injury initiates metabolic reprogramming in tubule cells that contributes to the development of chronic kidney disease (CKD). Exercise has been associated with beneficial effects in patients with CKD. Here we show that the induction of a myokine, irisin, improves kidney energy metabolism and prevents kidney damage. In response to kidney injury, mice with muscle-specific PGC-1? overexpression (mPGC-1?) exhibit reduced kidney damage and fibrosis. Metabolomics analysis reveals increased ATP production and improved energy metabolism in injured kidneys from mPGC-1? mice. We identify irisin as a serum factor that mediates these metabolic effects during progressive kidney injury by inhibiting TGF-? type 1 receptor. Irisin depletion from serum blunts the induction of oxygen consumption rate observed in tubule cells treated with mPGC-1? serum. In mice, recombinant irisin administration attenuates kidney damage and fibrosis and improves kidney functions. We suggest that myokine-mediated muscle-kidney crosstalk can suppress metabolic reprograming and fibrogenesis during kidney disease.
Project description:Uncoupling protein-2 (UCP2) regulates insulin secretion by controlling ATP levels in beta-cells. Although UCP2 deficiency improves glycemic control in mice, increased expression of UCP2 interferes with glucose-stimulated insulin secretion. These observations link UCP2 to beta-cell dysfunction in type 2 diabetes with a perplexing evolutionary role. We found higher residual serum insulin levels and blunted lipid metabolic responses in fasted ucp2(-/-) mice, supporting the concept that UCP2 evolved to suppress insulin effects and to accommodate the fuel switch to fatty acids during starvation. In the absence of UCP2, fasting initially promotes peripheral lipolysis and hepatic fat accumulation at less than expected rates but culminates in protracted steatosis, indicating diminished hepatic utilization and clearance of fatty acids. We conclude that UCP2-mediated control of insulin secretion is a physiologically relevant mechanism of the metabolic response to fasting.
Project description:Thioredoxin-interacting protein (Txnip) inhibits thioredoxin NADPH-dependent reduction of protein disulfides. Total Txnip knockout (TKO) mice adapted inappropriately to prolonged fasting by shifting fuel dependence of skeletal muscle and heart from fat and ketone bodies to glucose. TKO mice exhibited increased Akt signaling, insulin sensitivity, and glycolysis in oxidative tissues (skeletal muscle and hearts) but not in lipogenic tissues (liver and adipose tissue). The selective activation of Akt in skeletal muscle and hearts was associated with impaired mitochondrial fuel oxidation and the accumulation of oxidized (inactive) PTEN, whose activity depends on reduction of two critical cysteine residues. Whereas muscle- and heart-specific Txnip knockout mice recapitulated the metabolic phenotype exhibited by TKO mice, liver-specific Txnip knockout mice were similar to WT mice. Embryonic fibroblasts derived from knockout mice also accumulated oxidized (inactive) PTEN and had elevated Akt phosphorylation. In addition, they had faster growth rates and increased dependence on anaerobic glycolysis due to impaired mitochondrial fuel oxidation, and they were resistant to doxorubicin-facilitated respiration-dependent apoptosis. In the absence of Txnip, oxidative inactivation of PTEN and subsequent activation of Akt attenuated mitochondrial respiration, resulting in the accumulation of NADH, a competitive inhibitor of thioredoxin NADPH-reductive activation of PTEN. These findings indicate that, in nonlipogenic tissues, Txnip is required to maintain sufficient thioredoxin NADPH activity to reductively reactivate oxidized PTEN and oppose Akt downstream signaling.
Project description:Exercise under fasting conditions induces a switch to lipid metabolism, eliciting beneficial metabolic effects. Knowledge of signaling responses underlying metabolic adjustments in such conditions may help to identify therapeutic strategies. Therefore, we studied the effect of mild exercise on rats submitted to food withdrawal at thermoneutrality (28°C) for 3 days. Animals were housed at thermoneutrality rather than the standard housing temperature (22°C) to avoid beta-adrenergic signaling responses that themselves affect metabolism and well-being. Quantitative analysis of multi-organ mRNA levels, myofibers, and serum metabolites shows that this protocol (a) boosts fat oxidation in muscle and liver, (b) reduces lipogenesis and increases gluconeogenesis in liver, (c) increases serum acylcarnitines (especially C<sub>4</sub> OH) and ketone bodies and the use of the latter as fuel in muscle, (d) increases Type I myofibers, and (e) is associated with an increased thyroid hormone uptake and metabolism in muscle. In addition, stool microbiome DNA analysis revealed that food withdrawal dramatically alters the presence of bacterial genera associated with ketone metabolism. Taken together, this protocol induces a drastic switch toward increased lipid and ketone metabolism compared to exercise or food withdrawal alone, which may prove beneficial and may involve local thyroid hormones, which may be regarded as exercise mimetics.
Project description:Northern elephant seals (NES, Mirounga angustirostris) undergo an annual molt during which they spend ?40 days fasting on land with reduced activity and lose approximately one-quarter of their body mass. Reduced activity and muscle load in stereotypic terrestrial mammalian models results in decreased muscle mass and capacity for force production and aerobic metabolism. However, the majority of lost mass in fasting female NES is from fat while muscle mass is largely preserved. Although muscle mass is preserved, potential changes to the metabolic and contractile capacity are unknown. To assess potential changes in NES skeletal muscle during molt, we collected muscle biopsies from 6 adult female NES before the molt and after ?30 days at the end of the molt. Skeletal muscle was assessed for respiratory capacity using high resolution respirometry, and RNA was extracted to assess changes in gene expression. Despite a month of reduced activity, fasting, and weight loss, skeletal muscle respiratory capacity was preserved with no change in OXPHOS respiratory capacity. Molt was associated with 162 upregulated genes including those favoring lipid metabolism. We identified 172 downregulated genes including those coding for ribosomal proteins and genes associated with skeletal muscle force transduction and glucose metabolism. Following ?30 days of molt, NES skeletal muscle metabolic capacity is preserved although mechanotransduction may be compromised. In the absence of exercise stimulus, fasting-induced shifts in muscle metabolism may stimulate pathways associated with preserving the mass and metabolic capacity of slow oxidative muscle.
Project description:Evolutionary considerations suggest that the body has been optimized to perform at a high level in the fasted state when fatty acids and their ketone metabolites are a major fuel source for muscle cells. Because fasting is the most potent physiological stimulus for ketosis, we designed a study to determine the impact of intermittent fasting during endurance training on performance, and to elucidate the underlying cellular and molecular mechanisms. Male mice were randomly assigned to either ad libitum feeding or alternate-day fasting (AF) groups, and half of the mice in each diet group were trained daily on a treadmill for 1 month (45 minutes of running with increasing speed or incline each week). A run to exhaustion endurance test performed at the end of the training period revealed superior performance in the mice maintained on AF during training compared to mice fed ad libitum during training. VO2max was increased similarly by treadmill training in mice on AF or ad libitum diets, whereas respiratory exchange ratio (RER) was reduced in AF mice on fasting days and during running. Analyses of gene expression in liver and soleus tissues, and metabolomics analysis of blood suggest that the metabolic switch invoked by AF and potentiated by exercise strongly modulate molecular pathways involved in mitochondrial biogenesis, metabolism and cellular plasticity. Our findings demonstrate intermittent fasting engages metabolic and cellular signaling pathways that result in increased metabolic efficiency and endurance capacity. Overall design: Six month-old male C57BL/6J mice were randomly assigned to one of four groups: a sedentary control group fed ad libitum (CTRL); a sedentary group on alternate-day fasting (AF); a group with daily treadmill running exercise fed ad libitum (EX); and a group that ran every day on a treadmill while on AF (EXAF) during a 4-week study period.
Project description:Pairing the selective estrogen receptor modulator bazedoxifene (BZA) with estrogen as a tissue-selective estrogen complex (TSEC) is a novel menopausal therapy. We investigated estrogen, BZA and TSEC effects in preventing diabetisity in ovariectomized mice during high-fat feeding. Estrogen, BZA or TSEC prevented fat accumulation in adipose tissue, liver and skeletal muscle, and improved insulin resistance and glucose intolerance without stimulating uterine growth. Estrogen, BZA and TSEC improved energy homeostasis by increasing lipid oxidation and energy expenditure, and promoted insulin action by enhancing insulin-stimulated glucose disposal and suppressing hepatic glucose production. While estrogen improved metabolic homeostasis, at least partially, by increasing hepatic production of FGF21, BZA increased hepatic expression of Sirtuin1, PPAR? and AMPK activity. The metabolic benefits of BZA were lost in estrogen receptor-? deficient mice. Thus, BZA alone or in TSEC produces metabolic signals of fasting and caloric restriction and improves energy and glucose homeostasis in female mice.
Project description:The mechanisms underlying alterations in brain functions in response to physical exercise are not fully understood. The present study examined the central effect of irisin, a 112 amino acid polypeptide hormone secreted from the skeletal muscle after exercise, on the locomotion in rats. Central administration of irisin significantly increased the locomotion. Relative to control animals treated with IgG Fc peptide, rats receiving irisin demonstrated a marked increase in total travel distance, ambulatory counts and time, and vertical counts and time. These changes were associated with a significant decrease in resting time. Central treatment of irisin also induced significant increases in oxygen consumption, carbon dioxide production and heat production, indicating an increase in metabolic activity. Our study suggests that physical activity may signal to the central nervous system to coordinate locomotion with metabolic activity via irisin.