Types Of Muscle Atrophy Research Articles

CircTmeff1 Promotes Muscle Atrophy by Interacting with TDP-43 and Encoding A Novel TMEFF1-339aa Protein.

Skeletal muscle atrophy is a common clinical feature of many acute and chronic conditions. Circular RNAs (circRNAs) are covalently closed RNA transcripts that are involved in various physiological and pathological processes, but their role in muscle atrophy remains unknown. Global circRNA expression profiling indicated that circRNAs are involved in the pathophysiological processes of muscle atrophy. circTmeff1 is identified as a potential circRNA candidate that influences muscle atrophy. It is further identified that circTmeff1 is highly expressed in multiple types of muscle atrophy in vivo and in vitro. Moreover, the overexpression of circTmeff1 triggers muscle atrophy in vitro and in vivo, while the knockdown of circTmeff1 expression rescues muscle atrophy in vitro and in vivo. In particular, the knockdown of circTmeff1 expression partially rescues muscle mass in mice during established atrophic settings. Mechanistically, circTmeff1 directly interacts with TAR DNA-binding protein 43 (TDP-43) and promotes aggregation of TDP-43 in mitochondria, which triggers the release of mitochondrial DNA (mtDNA) into cytosol and activation of the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway. Unexpectedly, TMEFF1-339aa is identified as a novel protein encoded by circTmeff1 that mediates its pro-atrophic effects. Collectively, the inhibition of circTmeff1 represents a novel therapeutic approach for multiple types of skeletal muscle atrophy.

Identification of a novel small-molecule inhibitor of miR-29b attenuates muscle atrophy

Muscle atrophy is debilitating and can be induced by several stressors. Unfortunately, there are no effective pharmacological treatment until now. MicroRNA (miR)-29b is an important target that we identified to be commonly involved in multiple types of muscle atrophy. Although sequence-specific inhibition of miR-29b has been developed, in this study, we report a novelsmall-molecule miR-29b inhibitor that targets miR-29bhairpin precursor (pre-miR-29b) (Targapremir-29b-066 [TGP-29b-066]) considering both its three-dimensional structure and the thermodynamics of interaction between pre-miR-29b and the small molecule. This novel small-molecule inhibitor has been demonstrated to attenuate muscle atrophy induced by angiotensin II (Ang II), dexamethasone (Dex), and tumor necrosis factor α (TNF-α) in C2C12 myotubes, as evidenced by increase in the diameter of myotube and decrease in the expression of Atrogin-1 and MuRF-1. Moreover, it can also attenuate Ang II-induced muscle atrophy in mice, as evidenced by a similar increase in the diameter of myotube, reduced Atrogin-1 and MuRF-1 expression, AKT-FOXO3A-mTOR signaling activation, and decreased apoptosis and autophagy. In summary, we experimentally identified and demonstrated a novel small-molecule inhibitor of miR-29b that could act as a potential therapeutic agent for muscle atrophy.

Molecular Mechanisms Underlying Intensive Care Unit-Acquired Weakness and Sarcopenia.

Skeletal muscle is a highly adaptable organ, and its amount declines under catabolic conditions such as critical illness. Aging is accompanied by a gradual loss of muscle, especially when physical activity decreases. Intensive care unit-acquired weakness is a common and highly serious neuromuscular complication in critically ill patients. It is a consequence of critical illness and is characterized by a systemic inflammatory response, leading to metabolic stress, that causes the development of multiple organ dysfunction. Muscle dysfunction is an important component of this syndrome, and the degree of catabolism corresponds to the severity of the condition. The population of critically ill is aging; thus, we face another negative effect—sarcopenia—the age-related decline of skeletal muscle mass and function. Low-grade inflammation gradually accumulates over time, inhibits proteosynthesis, worsens anabolic resistance, and increases insulin resistance. The cumulative consequence is a gradual decline in muscle recovery and muscle mass. The clinical manifestation for both of the above conditions is skeletal muscle weakness, with macromolecular damage, and a common mechanism—mitochondrial dysfunction. In this review, we compare the molecular mechanisms underlying the two types of muscle atrophy, and address questions regarding possible shared molecular mechanisms, and whether critical illness accelerates the aging process.

Master Regulators of Muscle Atrophy: Role of Costamere Components.

The loss of muscle mass and force characterizes muscle atrophy in several different conditions, which share the expression of atrogenes and the activation of their transcriptional regulators. However, attempts to antagonize muscle atrophy development in different experimental contexts by targeting contributors to the atrogene pathway showed partial effects in most cases. Other master regulators might independently contribute to muscle atrophy, as suggested by our recent evidence about the co-requirement of the muscle-specific chaperone protein melusin to inhibit unloading muscle atrophy development. Furthermore, melusin and other muscle mass regulators, such as nNOS, belong to costameres, the macromolecular complexes that connect sarcolemma to myofibrils and to the extracellular matrix, in correspondence with specific sarcomeric sites. Costameres sense a mechanical load and transduce it both as lateral force and biochemical signals. Recent evidence further broadens this classic view, by revealing the crucial participation of costameres in a sarcolemmal “signaling hub” integrating mechanical and humoral stimuli, where mechanical signals are coupled with insulin and/or insulin-like growth factor stimulation to regulate muscle mass. Therefore, this review aims to enucleate available evidence concerning the early involvement of costamere components and additional putative master regulators in the development of major types of muscle atrophy.

Angiotensin II-induced muscle atrophy via PPARγ suppression is mediated by miR-29b

The activation of the renin-angiotensin system (RAS) induced by increased angiotensin II (AngII) levels has been implicated in muscle atrophy, which is involved in the pathogenesis of congestive heart failure. Although peroxisome proliferator-activated receptor gamma (PPARγ) activation can suppress RAS, the exact role of PPARγ in AngII-induced muscle atrophy is unclear. Here we identified PPARγ as a negative regulator of miR-29b, a microRNA that is able to promote multiple types of muscle atrophy. Suppression of miR-29b could prevent AngII-induced muscle atrophy both in vitro and in vivo. IGF1, PI3K(p85α), and Yin Yang 1 (YY1) were identified as target genes of miR-29b, and overexpression of these targets could rescue AngII-induced muscle atrophy. Importantly, inhibition of PPARγ was sufficient to induce muscle atrophy, while PPARγ overexpression could attenuate that. These data indicate that the PPARγ/miR-29b axis mediates AngII-induced muscle atrophy, and increasing PPARγ or inhibiting miR-29b represents a promising approach to counteract AngII-induced muscle atrophy.

Inhibition of lncRNA MAAT Controls Multiple Types of Muscle Atrophy by cis- and trans-Regulatory Actions

Muscle atrophy is associated with negative outcomes in a variety of diseases. Identification of a common therapeutic target would address a significant unmet clinical need. Here, we identify a long non-coding RNA (lncRNA) (muscle-atrophy-associated transcript, lncMAAT) as a common regulator of skeletal muscle atrophy. lncMAAT is downregulated in multiple types of muscle-atrophy models both invivo (denervation, Angiotensin II [AngII], fasting, immobilization, and aging-induced muscle atrophy) and invitro (AngII, H2O2, and tumor necrosis factor alpha [TNF-α]-induced muscle atrophy). Gain- and loss-of-function analysis both invitro and invivo reveals that downregulation of lncMAAT is sufficient to induce muscle atrophy, while overexpression of lncMAAT can ameliorate multiple types of muscle atrophy. Mechanistically, lncMAAT negatively regulates the transcription of miR-29b through SOX6 by a trans-regulatory module and increases the expression of the neighboring gene Mbnl1 by a cis-regulatory module. Therefore, overexpression of lncMAAT may represent a promising therapy for muscle atrophy induced by different stimuli.

Parvalbumin Affects Skeletal Muscle Trophism Through Modulation of Mitochondrial Calcium Uptake

Parvalbumin (PV) is a cytosolic EF-hand calcium-binding protein highly expressed in fast skeletal muscle fibers. By acting as a Ca2+ buffer, PV contributes to increase the relaxation rate in skeletal muscle fibers. More recently, PV has been described as one of the “atrogenes”, the collection of genes commonly up- and downregulated during both disuse and systemic types of muscle atrophy. Here we exploited the murine strain lacking PV (PV-/-) to explore the link between PV function as Ca2+ buffer and the control of muscle trophism. First, by using denervation as an acute model of atrophy, we found a lower muscle mass loss in PV-/- than in WT mice. Then, by acutely silencing and overexpressing PV in adult muscles of WT mice, we discovered that its downregulation was accompanied by hypertrophy and its upregulation by atrophy. Using compartment specific Ca2+ probes, we also explored three cellular compartments: cytosol, sarcoplasmic reticulum and mitochondria. The lack of PV was associated with an increased Ca2+ uptake in mitochondria, which could be supported by MCU complex components overexpression and an increased mitochondria volume. Intriguingly, MCU silencing abolished the hypertrophic effect of PV ablation on fiber size, suggesting a mitochondrial Ca2+-dependent mechanism of control of muscle trophism. This is corroborated by the induction of the expression of the mitochondrial Ca2+-dependent PGC1-a4 that promotes skeletal muscle hypertrophy. These data reveal a novel role of PV that links the control of cytosolic Ca2+ concentration to mitochondrial adaptations, ultimately leading to the control of muscle mass.

CRISPR/Cas9-Mediated miR-29b Editing as a Treatment of Different Types of Muscle Atrophy in Mice.

Muscle atrophy is the loss of skeletal muscle mass and strength in response to diverse catabolic stimuli. At present, no effective treatments except exercise have been shown to reduce muscle atrophy clinically. Here, we report that CRISPR/Cas9-mediated genome editing through local injection into gastrocnemius muscles or tibialis anterior muscle efficiently targets the biogenesis processing sites in pre-miR-29b. Invivo, this CRISPR-based treatment prevented the muscle atrophy induced by angiotensin II (AngII), immobilization, and denervation via activation of the AKT-FOXO3A-mTOR signaling pathway and protected against AngII-induced myocyte apoptosis in mice, leading to significantly increased exercise capacity. Our work establishes CRISPR/Cas9-based gene targeting on miRNA as a potential durable therapy for the treatment of muscle atrophy and expands the strategies available interrogating miRNA function invivo.

P5396CRISPR/Cas9 mediated miR-29b editing restores muscle atrophy and exercise capacity in mice

Abstract Background Muscle atrophy is the loss of skeletal muscle mass and strength in response to diversity catabolic stimuli, such as heart failure. At present, no effective treatment except exercise is validated on reducing multiple muscle atrophy clinically. We have recently reported that microRNA-29b (miR-29b) promotes multiple types of muscle atrophy. Purpose The goal of this study was to assess whether genome editing using a clustered regularly interspaced short palindromic repeat/Cas9 (CRISPR/Cas9) system can efficiently introduce loss-of-function mutations into the endogenous miR-29b in vivo and as a potential therapy by treating muscle atrophy. Methods We used lentivirus to express CRISPR-associated 9 and a CRISPR guide RNA targeting miR-29b. Mutagenesis rate of miR-29b and off-target mutagenesis were detected by T7 Endonuclease I (T7EI) Assay. The expression level of miR-29b were measured in vitro and vivo after administration of the virus by using qRT-PCR. After intramuscular administration of the virus, the angiotensin II (AngII), immobilization and denervation-induced muscle atrophy were performed. Then muscle function was assessed in exercise capacity, the appearance and weight of muscle, the size of the muscle fibers, molecular and cellular detection. Results Here, we report that CRISPR/Cas9 mediated genome editing through intramuscular administration efficiently targeting the biogenesis processing sites in pre-miR-29b. No off-target mutagenesis was detected in 10 selected sites. This CRISPR-based treatment resulted in decreased miR-29b levels specifically. In vivo, this CRISPR-based treatment could ameliorate the muscle atrophy induced by angiotensin II (AngII), immobilization and denervation via activation of PI3K-AKT-mTOR signaling pathway and protect against AngII-induced apoptosis in mice. Moreover, the exercise capacity is also significantly enhanced. Conclusion Our work establishes CRISPR/Cas9 based gene targeting on miRNA as a potential durable therapy for treatment of muscle atrophy and expands the strategies available interrogating miRNA function in vivo. Acknowledgement/Funding The grants from National Natural Science Foundation of China (81722008, 91639101 and 81570362 to JJ Xiao)

Do neurogenic and cancer-induced muscle atrophy follow common or divergent paths?

Skeletal muscle is a dynamic tissue capable of responding to a large variety of physiological stimuli by adjusting muscle fiber size, metabolism and function. However, in pathological conditions such as cancer and neural disorders, this finely regulated homeostasis is impaired leading to severe muscle wasting, reduced muscle fiber size (atrophy), and impaired function. These disease features develop due to enhanced protein breakdown, which relies on two major degradation systems: the ubiquitin-proteasome and the autophagy-lysosome. These systems are independently regulated by different signalling pathways, which in physiological conditions, determine protein and organelle turnover. However, alterations in one or both systems, as it happens in several disorders, leads to enhanced protein breakdown and muscle atrophy. Although this is a common feature in the different types of muscle atrophy, the relative contribution of each of these systems is still under debate. Here, we will briefly describe the regulation and the activity of the ubiquitin-proteasome and the autophagy-lysosome systems during muscle wasting. We will then discuss what we know regarding how these pathways are involved in cancer induced and in neurogenic muscle atrophy, highlighting common and divergent paths. It is now clear that there is no one unifying common mechanism that can be applied to all models of muscle loss. Detailed understanding of the pathways and proteolysis mechanisms involved in each model will hopefully help the development of drugs to counteract muscle wasting in specific conditions.

Abstract 16995: Inhibition of lncRNA MAAT Contributes to Multiple Types of Muscle Atrophy

Background: Skeletal muscle atrophy is the consequence of many diseases, such as denervation, long-term inactivity, excessive fasting, ageing, and heart failure. Recently, increasing studies have shown that long noncoding RNAs (lncRNAs) play an important role in myogenesis and adult skeletal muscle regeneration. However, if lncRNAs are responsible for muscle atrophy remains largely unclear. Hypothesis: We aimed to select and investigate the role of lncRNAs in muscle atrophy. Methods and Results: LncRNA arrays indicated that several lncRNA transcripts were changed during denervation-induced muscle atrophy in mice. After detecting the expression of lncRNAs in multiple types of muscle atrophy in vivo (denervation, Angiotensin II and fasting induced muscle atrophy) and in vitro (Angiotensin II, H 2 O 2 and TNFα induced muscle atrophy) by qRT-PCRs, we identified that MAAT (Muscle Atrophy-Associated Transcript) was down-regulated in multiple types of muscle atrophy. Then lentivirus of shRNA and overexpression of MAAT were further used to study the role of MAAT in muscle atrophy in vitro and in vivo . We found that knockdown of MAAT promoted muscle atrophy, whereas upregulating MAAT prevented multiple types of muscle atrophy. Mechanistically, we found that MAAT negatively regulated the transcription of microRNA-29b through SOX6, and that MAAT influenced the expression of neighbor gene-MBNL by a cis-regulatory module. Conclusions: Inhibition of LncRNA MAAT contributes to muscle atrophy by increasing miR-29b and repressing MBNL. Overexpressing MAAT might be a novel approach to counteract muscle atrophy.

Growth hormone and Insulin-like growth factor-I (IGF-I) modulate the expression of L-type amino acid transporters in the muscles of spontaneous dwarf rats and L6 and C2C12 myocytes

ObjectiveBranched-chain amino acids (BCAAs) have been reported to inhibit several types of muscle atrophy via the activation of the mechanistic target of rapamycin complex 1 (mTORC1). However, we previously found that BCAA did not activate mTORC1 in growth hormone (GH)-deficient spontaneous dwarf rats (SDRs), and that GH restored the stimulatory effect of BCAAs toward the mTORC1. The objective of this study was to determine whether GH or Insulin-like growth factor-I (IGF-I) stimulated the expression of L-type amino acid transporters (LATs) that delivered BCAAs, and whether LATs were involved in the mTORC1 activation. DesignAfter the continuous administration of GH, cross-sectional areas (CSAs) of muscle fibers and LAT mRNA levels in the skeletal muscles of SDRs were compared to those from the SDRs that received normal saline. The effect of GH and IGF-I on LAT mRNA levels were determined in L6 and C2C12 myocytes. The effects of 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid (BCH), a blocker for LATs, and LAT1 siRNA on mTORC1 activation and cell functions were examined in C2C12 cells. ResultsGH increased LAT1 and LAT4 mRNA levels in accordance with the increase in CSAs of muscle fibers in SDRs. IGF-I, and not GH, increased LAT1 mRNA levels in cultured L6 myocytes. IGF-I also increased LAT1 mRNA level in another myocyte line, C2C12. Furthermore, IGF-I reduced LAT3 and LAT4 mRNA levels in both cell lines. GH reduced LAT3 and LAT4 mRNA levels in L6 cells. BCH decreased basal C2C12 cell proliferation and reduced IGF-I-induced phosphorylation of 4E-BP1 and S6K, both of which are mTORC1 targets, but LAT1 siRNA did not affect the phosphorylation. This suggests that BCH may exert its effect via other pathway than LAT1.Conclusions: IGF-I increased LAT1 mRNA level in myocytes. However, the role of LAT1 in IGF-I-induced mTORC1 activation and cell functions remains unclear.

MiR-29b contributes to multiple types of muscle atrophy

A number of microRNAs (miRNAs, miRs) have been shown to play a role in skeletal muscle atrophy, but their role is not completely understood. Here we show that miR-29b promotes skeletal muscle atrophy in response to different atrophic stimuli in cells and in mouse models. miR-29b promotes atrophy of myotubes differentiated from C2C12 or primary myoblasts, and conversely, its inhibition attenuates atrophy induced by dexamethasone (Dex), TNF-α and H2O2 treatment. Targeting of IGF-1 and PI3K(p85α) by miR-29b is required for induction of muscle atrophy. In vivo, miR-29b overexpression is sufficient to promote muscle atrophy while inhibition of miR-29b attenuates atrophy induced by denervation and immobilization. These data suggest that miR-29b contributes to multiple types of muscle atrophy via targeting of IGF-1 and PI3K(p85α), and that suppression of miR-29b may represent a therapeutic approach for muscle atrophy induced by different stimuli.

Professor Junjie Xiao: research-teaching nexus creates a new platform in the field of non-coding RNA

Junjie Xiao ( Figure 1 ), a Professor of School of Life Sciences, Shanghai University, has recently published an important original article entitled “miR-29b contributes to multiple types of muscle atrophy” in Nature Communications as a corresponding author, therefore School of Life Sciences, Shanghai University has made a breakthrough by being the corresponding institution of a publication in Nature’s sub-journal for the first time. Professor Xiao’s laboratory is situated in the School of Life Science Building at Shanghai University, and the perfect combination of well-arranged workbenches, scientific instruments and focused researchers creates a vibrant academic atmosphere.

Abstract 206: microRNA-29b Contributes to Multiple Types of Muscle Atrophy

Objective: Skeletal muscle atrophy has been observed in a significant proportion of heart failure patients while little is known about the mechanisms underlying muscle atrophy, especially in multiple types of muscle atrophy. MicroRNAs (miRNAs, miRs) are among key participants in gene regulatory networks and their dysregulation contribute to lots of diseases. However, miRNAs responsible for multiple types of muscle atrophy are unclear. Methods and Result: miRNAs were screened by miRNA arrays and were further verified by real-time reverse transcription polymerase chain reaction with the gastrocnemius sample from denervation -induce muscle atrophy. miR-130b, miR-212, miR-21, miR-221/222, miR-223 and miR-29b were upregulated >3 fold in gastrocnemius samples from denervation mice than that of sham group. However, only miR-29b presented a common change (upregulated >3) in other types of muscle atrophy models including dexamethasone-induced and fasting-induced muscle atrophy. Over-expression of miR-29b in gastrocnemius by intramuscular injection with agomiR-29b significantly promoted muscle atrophy, which is evidenced by the change in morphology (the diameter of myofiber was decrease by 60%) and increased atrophy-related genes including Atrogin-1 and MuRF-1 (upregulated for 1.5 folds and 1.4 folds, respectively). This in vivo data suggest that miR-29b is sufficient to induce muscle atrophy. In multiple types of muscle atrophy C2C12 cell models (dexamethasone, TNF-alpha and H2O2 induced), miR-29b was increased while inhibition of miR-29b could prevent that effects. Using TargetScan software, we found that IGF1 and PI3Ka were potential target genes for miR-29b, which was further validated by luciferase assays and western blotting. Moreover, over-expression of IGF1 or PI3Ka ameliorated muscle atrophy caused by miR-29b overexpression, indicating that IGF1 and PI3Ka are two target genes responsible for miR-29b’s pro-atrophy effects in muscle. Conclusions: Our data indicated that via targeting IGF1 and PI3Ka. Inhibition of miR-29b might represent a novel therapy for multiple types of muscle atrophy including in heart failure.

Neuronal NOS is dislocated during muscle atrophy in amyotrophic lateral sclerosis

Previously, we demonstrated that neuronal nitric oxide synthase (nNOS) is activated and promotes muscle atrophy in skeletal muscle during tail suspension, a model of unloading and denervation. Here, we examined patients with amyotrophic lateral sclerosis (ALS) and mutant (H46R) SOD1 transgenic (Tg) mice model using immunohistochemistry, Western blotting and real time PCR. We found cytoplasmic nNOS staining of angulated muscle fibers in patients with ALS. We also examined mutant SOD1 Tg mice and found cytoplasmic nNOS staining even before the onset of clinical muscle atrophy. In the Tg mice, nNOS was largely extracted with 100 mM NaCl and barely detected in the pellet fraction, suggesting fragile anchoring of nNOS to the sarcolemma. We also showed an elevated expression of atrogin-1, key molecules in muscle atrophy at the end stage. A common nNOS dislocation/atrogin-1/muscle atrophy pathway among tail suspension, denervation and ALS is suggested. nNOS modulation therapy may be beneficial in several types of muscle atrophy.

Anterior and posterior decompressive surgery for progressive amyotrophy associated with cervical spondylosis: a retrospective study of 51 patients

The aims of this study were to review the clinicoradiological findings in patients who underwent decompressive surgery for proximal and distal types of muscle atrophy caused by cervical spondylosis and to discuss the outcome and techniques of surgical intervention. Fifty-one patients (43 men and 8 women) with proximal (37, with arm drop) and distal muscle atrophy (14, with wrist drop) underwent cervical decompression (39 anterior decompressions and 12 open-door C3-7 laminoplasties with microsurgical foraminotomy) for muscle weakness in the upper extremities. The clinical course, type of spinal cord compression, abnormal signal intensity on high-resolution MR imaging, and postdecompression improvement in muscle power were reviewed at a mean follow-up of 2.6 years (range 0.8-9.4 years). The most commonly affected vertebrae were C4-5 and C5-6, and C5-6 and C6-7 in patients with proximal or distal muscle atrophy, respectively; the respective numbers of affected vertebrae were 1.5 and 2.2. Transaxial MR imaging showed medial compression of the spinal cord in 20 patients (in 12 with proximal and 8 with distal muscle atrophy), paramedial compression in 22 (17 and 5 patients, respectively), and foraminal compression in 9 (8 and 1 patient, respectively). Increased signal intensity on MR imaging was observed in 85.0, 22.7, and 11.1% of cases of medial, paramedial, and foraminal compression, respectively. Increased signal intensity at the affected muscle segment level was observed in 52.9, 40.0, and 0% of cases, respectively. Sixty-two percent of patients with proximal muscle atrophy gained 1 or more grades of muscle power on manual muscle testing (MMT), whereas 64.3% with distal muscle atrophy failed to gain even 1 grade of improvement. The recovery of muscle power correlated with disease duration and the percent voltage of Erb point or wrist-stimulated muscle evoked potentials but not with preoperative MMT, longitudinal range of spinal cord compression, signal change on T2-weighted MR imaging, or surgical procedure. Surgical outcome in patients with distal muscle atrophy was inferior to that in patients with proximal atrophy. The distal type was characterized by a long preoperative period, a greater number of cervical spine misalignments, a narrow spinal canal, and increased signal intensity on T2-weighted MR imaging. It is essential to perform a careful neurological evaluation, including sensory examination of the lower limbs, as well as neuroradiological and neurophysiological assessments to avoid confusion with motor neuron disease and to detect the coexistence of amyotrophic lateral sclerosis, especially when surgical treatment of cervical spondylosis is planned. The results of careful physical examination, MR imaging studies, and electromyography studies should be comprehensively evaluated to ascertain the pathophysiology of the muscle atrophy. It is very important to distinguish the pathophysiology caused by nerve root impingements from anterior horn dysfunction when making decisions about treatment strategy. Surgical treatment--with or without foraminotomy--for amyotrophy in cervical spondylosis requires urgent action with regard to human neuroanatomy and neural innervation of the paralyzed muscles.

Upregulation of myostatin gene expression in streptozotocin-induced type 1 diabetes mice is attenuated by insulin

Myostatin is a strong inhibitor of muscle growth, and its expression is increased in several types of muscle atrophy. However, whether or not myostatin expression is altered in muscle atrophy associated with type 1 diabetes (T1D) remains uncertain. In this study, we provided experimental evidence to show that myostatin mRNA increased in the early stage of T1D but came back to control levels later on. This expression pattern was closely correlated with the loss of body weight and atrogin-1 expression. Furthermore, induction of myostatin expression could be attenuated by insulin in T1D mice. Taken together, our findings indicate that the upregulation of myostatin expression most likely contributes to the muscle atrophy process during insulin deficiency.

Meta-analysis of expression signatures of muscle atrophy: gene interaction networks in early and late stages

BackgroundSkeletal muscle mass can be markedly reduced through a process called atrophy, as a consequence of many diseases or critical physiological and environmental situations. Atrophy is characterised by loss of contractile proteins and reduction of fiber volume. Although in the last decade the molecular aspects underlying muscle atrophy have received increased attention, the fine mechanisms controlling muscle degeneration are still incomplete. In this study we applied meta-analysis on gene expression signatures pertaining to different types of muscle atrophy for the identification of novel key regulatory signals implicated in these degenerative processes.ResultsWe found a general down-regulation of genes involved in energy production and carbohydrate metabolism and up-regulation of genes for protein degradation and catabolism. Six functional pathways occupy central positions in the molecular network obtained by the integration of atrophy transcriptome and molecular interaction data. They are TGF-β pathway, apoptosis, membrane trafficking/cytoskeleton organization, NFKB pathways, inflammation and reorganization of the extracellular matrix. Protein degradation pathway is evident only in the network specific for muscle short-term response to atrophy. TGF-β pathway plays a central role with proteins SMAD3/4, MYC, MAX and CDKN1A in the general network, and JUN, MYC, GNB2L1/RACK1 in the short-term muscle response network.ConclusionOur study offers a general overview of the molecular pathways and cellular processes regulating the establishment and maintenance of atrophic state in skeletal muscle, showing also how the different pathways are interconnected. This analysis identifies novel key factors that could be further investigated as potential targets for the development of therapeutic treatments. We suggest that the transcription factors SMAD3/4, GNB2L1/RACK1, MYC, MAX and JUN, whose functions have been extensively studied in tumours but only marginally in muscle, appear instead to play important roles in regulating muscle response to atrophy.

The IκB kinases IKKα and IKKβ are necessary and sufficient for skeletal muscle atrophy

Nuclear factor-kappaB (NF-kappaB) signaling is necessary for many types of muscle atrophy, yet only some of the required components have been identified. Gene transfer of a dominant negative (d.n.) IKKbeta into rat soleus muscles showed complete inhibition of 7-day disuse-induced activation of a kappaB reporter gene, while overexpression of wild-type (w.t.) IKKbeta did not. Overexpression of a d.n. IKKbeta-EGFP fusion protein showed that atrophy was inhibited by 50%, indicating that IKKbeta is required for the atrophy process. Overexpression of constitutively active (c.a.) IKKbeta-EGFP showed a marked increase in NF-kappaB activity and a decrease in fiber size of weight-bearing soleus muscles, while muscles overexpressing w.t. IKKbeta-HA had no effect. The same results were found for IKKalpha; overexpression of a d.n. form of the protein decreased unloading-induced NF-kappaB activation and inhibited atrophy by 50%, while overexpression of the w.t. protein had no effect. Overexpression of a c.a. IKKalpha-EGFP fusion protein showed that IKKalpha was sufficient to activate NF-kappaB activity and induce fiber atrophy in muscle. Overexpression of d.n. IKKbeta plus d.n. IKKalpha showed an additive effect on the inhibition of disuse atrophy (70%), suggesting that both kinases of the IKK complex are required for muscle atrophy. These data show that both IKKalpha and IKKbeta are necessary and sufficient for physiological muscle atrophy.