The quality of mitochondria in skeletal muscle is essential for maintaining metabolic homeostasis during adaptive stress responses. However, the precise control mechanism of muscle mitochondrial quality and its physiological impacts remain unclear. Here, we demonstrate that FUNDC1, a mediator of mitophagy, plays a critical role in controlling muscle mitochondrial quality as well as metabolic homeostasis. Skeletal-muscle-specific ablation of FUNDC1 in mice resulted in LC3-mediated mitophagy defect, leading to impaired mitochondrial energetics. This caused decreased muscle fat utilization and endurance capacity during exercise. Interestingly, mice lacking muscle FUNDC1 were protected against high-fat-diet-induced obesity with improved systemic insulin sensitivity and glucose tolerance despite reduced muscle mitochondrial energetics. Mechanistically, FUNDC1 deficiency elicited a retrograde response in muscle that upregulated FGF21 expression, thereby promoting the thermogenic remodeling of adipose tissue. Thus, these findings reveal a pivotal role of FUNDC1-dependent mitochondrial quality control in mediating the muscle-adipose dialog to regulate systemic metabolism.

Upon adaption of skeletal muscle to physiological and pathophysiological stimuli, muscle fiber type and mitochondrial function are coordinately regulated. Recent studies have identified pathways involved in control of contractile proteins of oxidative‐type fibers. However, the mechanism for coupling of mitochondrial function to the muscle contractile machinery during fiber type transition remains unknown. Here, we show that the expression of the genes encoding type I myosins, Myh7/Myh7b and their intronic miR‐208b/miR‐499, parallels mitochondrial function during fiber type transitions. Using in vivo approaches in mice, we found that miR‐499 drives a PGC‐1α‐dependent mitochondrial oxidative metabolism program to match shifts in slow‐twitch muscle fiber composition. Mechanistically, miR‐499 directly targets Fnip1, an AMP‐activated protein kinase (AMPK)‐interacting protein that negatively regulates AMPK, a known activator of PGC‐1α. Inhibition of Fnip1 reactivated AMPK/PGC‐1α signaling and mitochondrial function in myocytes. Restoration of the expression of miR‐499 in the mdx mouse model of Duchenne muscular dystrophy (DMD) reduced the severity of DMD. Thus, we have identified a miR‐499/Fnip1/AMPK circuit that can serve as a mechanism to couple muscle fiber type and mitochondrial function.

Edited by Jeffrey PessinLactate dehydrogenase (LDH) catalyzes the interconversion of pyruvate and lactate, which are critical fuel metabolites of skeletal muscle particularly during exercise. However, the physiological relevance of LDH remains poorly understood. Here we show that Ldhb expression is induced by exercise in human muscle and negatively correlated with changes in intramuscular pH levels, a marker of lactate production, during isometric exercise. We found that the expression of Ldhb is regulated by exerciseinduced peroxisome proliferator-activated receptor ␥ coactivator 1␣ (PGC-1␣). Ldhb gene promoter reporter studies demonstrated that PGC-1␣ activates Ldhb gene expression through multiple conserved estrogen-related receptor (ERR) and myocyte enhancer factor 2 (MEF2) binding sites. Transgenic mice overexpressing Ldhb in muscle (muscle creatine kinase (MCK)-Ldhb) exhibited increased exercise performance and enhanced oxygen consumption during exercise. MCK-Ldhb muscle was shown to have enhanced mitochondrial enzyme activity and increased mitochondrial gene expression, suggesting an adaptive oxidative muscle transformation. In addition, mitochondrial respiration capacity was increased and lactate production decreased in MCK-Ldhb skeletal myotubes in culture. Together, these results identified a previously unrecognized Ldhb-driven alteration in muscle mitochondrial function and suggested a mechanism for the adaptive metabolic response induced by exercise training.Muscle fitness and resistance to fatigue depend strongly on the capacity to burn the fuels, including fatty acids and glucose, to meet ATP demands (1-5). Exercise training is effective in improving muscle fitness by promoting favorable muscle metabolic reprograming including capacity for fuel burning, mitochondrial ATP production, and contraction (6 -13). Conversely, many chronic diseases, including obesity, diabetes, muscular diseases, and aging, are associated with decreased muscle fitness, contributing to a vicious cycle of inactivity and further promoting the progression of chronic diseases (6 -8, 11, 12, 14). Thus, a better understanding of the molecular regulatory pathways involved in the beneficial effects of exercise training on muscle fuel metabolism could yield novel therapeutic targets aimed at the prevention or treatment of diseases associated with muscle bioenergetics defects.The molecular and cellular mechanisms of skeletal muscle adaptation to exercise training are unclear. Exercise traininginduced adaptations in skeletal muscle are reflected, in part, by changes in transcriptional response and metabolite flux (1,2,4,5,11,15,16). Previous studies have demonstrated that the PGC-1␣ 3 transcriptional regulatory circuit, including the nuclear receptors PPAR and ERR, is a key transducer of exercise-responsive gene expression. The PGC-1␣ circuit regulates a broad array of genes involved in mitochondrial biogenesis and fuel metabolism (17)(18)(19)(20)(21)(22)(23)(24)(25). Evidence is also emerging that manipulation of metabolic enzyme or...

The cytoplasmic coat protein complex-II (COPII) is evolutionarily conserved machinery that is essential for efficient trafficking of protein and lipid cargos. How the COPII machinery is regulated to meet the metabolic demand in response to alterations of the nutritional state remains largely unexplored, however. Here, we show that dynamic changes of COPII vesicle trafficking parallel the activation of transcription factor X-box binding protein 1 (XBP1s), a critical transcription factor in handling cellular endoplasmic reticulum (ER) stress in both live cells and mouse livers upon physiological fluctuations of nutrient availability. Using live-cell imaging approaches, we demonstrate that XBP1s is sufficient to promote COPII-dependent trafficking, mediating the nutrient stimulatory effects. Chromatin immunoprecipitation (ChIP) coupled with high-throughput DNA sequencing (ChIP-seq) and RNA-sequencing analyses reveal that nutritional signals induce dynamic XBP1s occupancy of promoters of COPII traffic-related genes, thereby driving the COPII-mediated trafficking process. Liver-specific disruption of the inositol-requiring enzyme 1α (IRE1α)-XBP1s signaling branch results in diminished COPII vesicle trafficking. Reactivation of XBP1s in mice lacking hepatic IRE1α restores COPII-mediated lipoprotein secretion and reverses the fatty liver and hypolipidemia phenotypes. Thus, our results demonstrate a previously unappreciated mechanism in the metabolic control of liver protein and lipid trafficking: The IRE1α-XBP1s axis functions as a nutrient-sensing regulatory nexus that integrates nutritional states and the COPII vesicle trafficking. COPII | metabolic sensing | XBP1s | nutrient availability | liver steatosis T he cytoplasmic coat protein complex-II (COPII) is evolutionarily conserved secretory machinery that is essential for cellular protein and lipid trafficking through cargo sorting and vesicle formation at the endoplasmic reticulum (ER) (1-4). The vast majority of proteins and lipids exported from the ER require the COPII secretory machinery. The assembly of COPII-coated vesicles for facilitating the transport of cellular cargos has been demonstrated to be a highly complex process (1-6). Activated small GTPase SAR1 localizes to the specialized ER exit sites and initiates the COPII coat assembly, by first recruiting the inner coat formed by the heterodimer SEC23/SEC24, followed by the outer coat heterotetramer SEC13/SEC31, to deform the ER membrane and eventually produce carrier vesicles (2, 4, 7-9). Mutations in COPII components or accessory factors have been implicated in several human genetic diseases, including chylomicron retention disease, congenital dyserythropoietic anemia type II, and cranio-lenticulosutural dysplasia (10-14). However, it remains largely unexplored how the COPII machinery is regulated to meet the cellular secretory demand in response to various physiological stimuli.As a metabolically active tissue, the liver possesses a remarkable adaptive capacity to secrete lipids and proteins according to...

Objectives To compare the transfer accuracy of two digital transfer trays, the three-dimensional printed (3D printed) tray and the vacuum-formed tray, in the indirect bonding of labial brackets. Materials and Methods Ten digital dental models were constructed by oral scans using an optical scanning system. 3D printed trays and vacuum-formed trays were obtained through the 3Shape indirect bonding system and rapid prototyping technology (10 in each group). Then labial brackets were transferred to 3D printed models, and the models with final bracket positioning were scanned. Linear (mesiodistal, vertical, buccolingual) and angular (angulation, torque, rotation) transfer errors were measured using GOM Inspect software. The mean transfer errors and prevalence of clinically acceptable errors (linear errors of ≤0.5 mm and angular errors of ≤2°) of two digital trays were compared using the Mann-Whitney U-test and the Chi-square test, respectively. Results The 3D printed tray had a lower mean mesiodistal transfer error (P < .01) and a higher prevalence of rotation error within the limit of 2° (P = .03) than did the vacuum-formed tray. Linear errors within 0.5 mm were higher than 90% for both groups, while torque errors within 2° were lowest at 50.9% and 52.9% for the 3D printed tray and vacuum-formed tray, respectively. Both groups had a directional bias toward the occlusal, mesial, and buccal. Conclusions The 3D printed tray generally scored better in terms of transfer accuracy than did the vacuum-formed tray. Both types of trays had better linear control than angular control of brackets.

Mitochondria are essential for maintaining skeletal muscle metabolic homeostasis during adaptive response to a myriad of physiologic or pathophysiological stresses. The mechanisms by which mitochondrial function and contractile fiber type are concordantly regulated to ensure muscle function remain poorly understood. Evidence is emerging that the Folliculin interacting protein 1 (Fnip1) is involved in skeletal muscle fiber type specification, function, and disease. In this study, Fnip1 was specifically expressed in skeletal muscle in Fnip1-transgenic (Fnip1Tg) mice. Fnip1Tg mice were crossed with Fnip1-knockout (Fnip1KO) mice to generate Fnip1TgKO mice expressing Fnip1 only in skeletal muscle but not in other tissues. Our results indicate that, in addition to the known role in type I fiber program, FNIP1 exerts control upon muscle mitochondrial oxidative program through AMPK signaling. Indeed, basal levels of FNIP1 are sufficient to inhibit AMPK but not mTORC1 activity in skeletal muscle cells. Gain-of-function and loss-of-function strategies in mice, together with assessment of primary muscle cells, demonstrated that skeletal muscle mitochondrial program is suppressed via the inhibitory actions of FNIP1 on AMPK. Surprisingly, the FNIP1 actions on type I fiber program is independent of AMPK and its downstream PGC-1α. These studies provide a vital framework for understanding the intrinsic role of FNIP1 as a crucial factor in the concerted regulation of mitochondrial function and muscle fiber type that determine muscle fitness.

Our earlier findings indicate that the long non-coding RNA MALAT1 promotes colorectal cancer (CRC) cell proliferation, invasion and metastasis in vitro and in vivo by increasing expression of AKAP-9. In the present study, we investigated the molecular mechanism by which MALAT1 enhances AKAP9 expression in CRC SW480 cells. We found that MALAT1 interacts with both SRPK1 and SRSF1. MALAT1 increases AKAP-9 expression by promoting SRPK1-catalyzed SRSF1 phosphorylation. Following MALAT1 knockdown, overexpression of SRPK1 was sufficient to restore SRSF1 phosphorylation and AKAP-9 expression to a level that promoted cell proliferation, invasion and migration in vitro. Conversely, SRPK1 knockdown after overexpression of MALAT1 in SW480 cells diminished SRSF1 phosphorylation and AKAP-9 expression and suppressed cell proliferation, invasion and migration in vitro. These findings suggest MALAT1 increases AKAP-9 expression by promoting SRPK1-catalyzed SRSF1 phosphorylation in CRC cells. These results reveal a novel molecular mechanism by which MALAT1 regulates AKAP-9 expression in CRC cells.

Mitochondrial proteolysis is an evolutionarily conserved quality-control mechanism to maintain proper mitochondrial integrity and function. However, the physiological relevance of stress-induced impaired mitochondrial protein quality remains unclear. Here, we demonstrate that LONP1, a major mitochondrial protease resides in the matrix, plays a role in controlling mitochondrial function as well as skeletal muscle mass and strength in response to muscle disuse. In humans and mice, disuse-related muscle loss is associated with decreased mitochondrial LONP1 protein. Skeletal muscle-specific ablation of LONP1 in mice resulted in impaired mitochondrial protein turnover, leading to mitochondrial dysfunction. This caused reduced muscle fiber size and strength. Mechanistically, aberrant accumulation of mitochondrial-retained protein in muscle upon loss of LONP1 induces the activation of autophagy-lysosome degradation program of muscle loss. Overexpressing a mitochondrial-retained mutant ornithine transcarbamylase (ΔOTC), a known protein degraded by LONP1, in skeletal muscle induces mitochondrial dysfunction, autophagy activation, and cause muscle loss and weakness. Thus, these findings reveal a role of LONP1-dependent mitochondrial protein quality-control in safeguarding mitochondrial function and preserving skeletal muscle mass and strength, and unravel a link between mitochondrial protein quality and muscle mass maintenance during muscle disuse.