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    Glycolytic-to-oxidative fiber-type switch and mTOR signaling activation are early-onset features of SBMA muscle modified by high-fat diet. Rocchi Anna,Milioto Carmelo,Parodi Sara,Armirotti Andrea,Borgia Doriana,Pellegrini Matteo,Urciuolo Anna,Molon Sibilla,Morbidoni Valeria,Marabita Manuela,Romanello Vanina,Gatto Pamela,Blaauw Bert,Bonaldo Paolo,Sambataro Fabio,Robins Diane M,Lieberman Andrew P,Sorarù Gianni,Vergani Lodovica,Sandri Marco,Pennuto Maria Acta neuropathologica Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by the expansion of a polyglutamine tract in the androgen receptor (AR). The mechanism by which expansion of polyglutamine in AR causes muscle atrophy is unknown. Here, we investigated pathological pathways underlying muscle atrophy in SBMA knock-in mice and patients. We show that glycolytic muscles were more severely affected than oxidative muscles in SBMA knock-in mice. Muscle atrophy was associated with early-onset, progressive glycolytic-to-oxidative fiber-type switch. Whole genome microarray and untargeted lipidomic analyses revealed enhanced lipid metabolism and impaired glycolysis selectively in muscle. These metabolic changes occurred before denervation and were associated with a concurrent enhancement of mechanistic target of rapamycin (mTOR) signaling, which induced peroxisome proliferator-activated receptor γ coactivator 1 alpha (PGC1α) expression. At later stages of disease, we detected mitochondrial membrane depolarization, enhanced transcription factor EB (TFEB) expression and autophagy, and mTOR-induced protein synthesis. Several of these abnormalities were detected in the muscle of SBMA patients. Feeding knock-in mice a high-fat diet (HFD) restored mTOR activation, decreased the expression of PGC1α, TFEB, and genes involved in oxidative metabolism, reduced mitochondrial abnormalities, ameliorated muscle pathology, and extended survival. These findings show early-onset and intrinsic metabolic alterations in SBMA muscle and link lipid/glucose metabolism to pathogenesis. Moreover, our results highlight an HFD regime as a promising approach to support SBMA patients. 10.1007/s00401-016-1550-4
    The Role of Metabolic Remodeling in Macrophage Polarization and Its Effect on Skeletal Muscle Regeneration. De Santa Francesca,Vitiello Laura,Torcinaro Alessio,Ferraro Elisabetta Antioxidants & redox signaling Macrophages are crucial for tissue homeostasis. Based on their activation, they might display classical/M1 or alternative/M2 phenotypes. M1 macrophages produce pro-inflammatory cytokines, reactive oxygen species (ROS), and nitric oxide (NO). M2 macrophages upregulate arginase-1 and reduce NO and ROS levels; they also release anti-inflammatory cytokines, growth factors, and polyamines, thus promoting angiogenesis and tissue healing. Moreover, M1 and M2 display key metabolic differences; M1 polarization is characterized by an enhancement in glycolysis and in the pentose phosphate pathway (PPP) along with a decreased oxidative phosphorylation (OxPhos), whereas M2 are characterized by an efficient OxPhos and reduced PPP. The glutamine-related metabolism has been discovered as crucial for M2 polarization. , flux discontinuities in the Krebs cycle are considered additional M1 features; they lead to increased levels of immunoresponsive gene 1 and itaconic acid, to isocitrate dehydrogenase 1-downregulation and to succinate, citrate, and isocitrate over-expression. A macrophage classification problem, particularly , originating from a gap in the knowledge of the several intermediate polarization statuses between the M1 and M2 extremes, characterizes this field. Moreover, the detailed features of metabolic reprogramming crucial for macrophage polarization are largely unknown; in particular, the role of β-oxidation is highly controversial. Manipulating the metabolism to redirect macrophage polarization might be useful in various pathologies, including an efficient skeletal muscle regeneration. Unraveling the complexity pertaining to metabolic signatures that are specific for the different macrophage subsets is crucial for identifying new compounds that are able to trigger macrophage polarization and that might be used for therapeutical purposes. 10.1089/ars.2017.7420
    A direct HDAC4-MAP kinase crosstalk activates muscle atrophy program. Choi Moon-Chang,Cohen Todd J,Barrientos Tomasa,Wang Bin,Li Ming,Simmons Bryan J,Yang Jeong Soo,Cox Gregory A,Zhao Yingming,Yao Tso-Pang Molecular cell Prolonged deficits in neural input activate pathological muscle remodeling, leading to atrophy. In denervated muscle, activation of the atrophy program requires HDAC4, a potent repressor of the master muscle transcription factor MEF2. However, the signaling mechanism that connects HDAC4, a protein deacetylase, to the atrophy machinery remains unknown. Here, we identify the AP1 transcription factor as a critical target of HDAC4 in neurogenic muscle atrophy. In denervated muscle, HDAC4 activates AP1-dependent transcription, whereas AP1 inactivation recapitulates HDAC4 deficiency and blunts the muscle atrophy program. We show that HDAC4 activates AP1 independently of its canonical transcriptional repressor activity. Surprisingly, HDAC4 stimulates AP1 activity by activating the MAP kinase cascade. We present evidence that HDAC4 binds and promotes the deacetylation and activation of a key MAP3 kinase, MEKK2. Our findings establish an HDAC4-MAPK-AP1 signaling axis essential for neurogenic muscle atrophy and uncover a direct crosstalk between acetylation- and phosphorylation-dependent signaling cascades. 10.1016/j.molcel.2012.04.025
    Acylated and unacylated ghrelin impair skeletal muscle atrophy in mice. Porporato Paolo E,Filigheddu Nicoletta,Reano Simone,Ferrara Michele,Angelino Elia,Gnocchi Viola F,Prodam Flavia,Ronchi Giulia,Fagoonee Sharmila,Fornaro Michele,Chianale Federica,Baldanzi Gianluca,Surico Nicola,Sinigaglia Fabiola,Perroteau Isabelle,Smith Roy G,Sun Yuxiang,Geuna Stefano,Graziani Andrea The Journal of clinical investigation Cachexia is a wasting syndrome associated with cancer, AIDS, multiple sclerosis, and several other disease states. It is characterized by weight loss, fatigue, loss of appetite, and skeletal muscle atrophy and is associated with poor patient prognosis, making it an important treatment target. Ghrelin is a peptide hormone that stimulates growth hormone (GH) release and positive energy balance through binding to the receptor GHSR-1a. Only acylated ghrelin (AG), but not the unacylated form (UnAG), can bind GHSR-1a; however, UnAG and AG share several GHSR-1a-independent biological activities. Here we investigated whether UnAG and AG could protect against skeletal muscle atrophy in a GHSR-1a-independent manner. We found that both AG and UnAG inhibited dexamethasone-induced skeletal muscle atrophy and atrogene expression through PI3Kβ-, mTORC2-, and p38-mediated pathways in myotubes. Upregulation of circulating UnAG in mice impaired skeletal muscle atrophy induced by either fasting or denervation without stimulating muscle hypertrophy and GHSR-1a-mediated activation of the GH/IGF-1 axis. In Ghsr-deficient mice, both AG and UnAG induced phosphorylation of Akt in skeletal muscle and impaired fasting-induced atrophy. These results demonstrate that AG and UnAG act on a common, unidentified receptor to block skeletal muscle atrophy in a GH-independent manner. 10.1172/JCI39920
    Irisin is a pro-myogenic factor that induces skeletal muscle hypertrophy and rescues denervation-induced atrophy. Reza Musarrat Maisha,Subramaniyam Nathiya,Sim Chu Ming,Ge Xiaojia,Sathiakumar Durgalakshmi,McFarlane Craig,Sharma Mridula,Kambadur Ravi Nature communications Exercise induces expression of the myokine irisin, which is known to promote browning of white adipose tissue and has been shown to mediate beneficial effects following exercise. Here we show that irisin induces expression of a number of pro-myogenic and exercise response genes in myotubes. Irisin increases myogenic differentiation and myoblast fusion via activation of IL6 signaling. Injection of irisin in mice induces significant hypertrophy and enhances grip strength of uninjured muscle. Following skeletal muscle injury, irisin injection improves regeneration and induces hypertrophy. The effects of irisin on hypertrophy are due to activation of satellite cells and enhanced protein synthesis. In addition, irisin injection rescues loss of skeletal muscle mass following denervation by enhancing satellite cell activation and reducing protein degradation. These data suggest that irisin functions as a pro-myogenic factor in mice. 10.1038/s41467-017-01131-0
    Denervation-activated STAT3-IL-6 signalling in fibro-adipogenic progenitors promotes myofibres atrophy and fibrosis. Madaro Luca,Passafaro Magda,Sala David,Etxaniz Usue,Lugarini Francesca,Proietti Daisy,Alfonsi Maria Vittoria,Nicoletti Chiara,Gatto Sole,De Bardi Marco,Rojas-García Ricardo,Giordani Lorenzo,Marinelli Sara,Pagliarini Vittoria,Sette Claudio,Sacco Alessandra,Puri Pier Lorenzo Nature cell biology Fibro-adipogenic progenitors (FAPs) are typically activated in response to muscle injury, and establish functional interactions with inflammatory and muscle stem cells (MuSCs) to promote muscle repair. We found that denervation causes progressive accumulation of FAPs, without concomitant infiltration of macrophages and MuSC-mediated regeneration. Denervation-activated FAPs exhibited persistent STAT3 activation and secreted elevated levels of IL-6, which promoted muscle atrophy and fibrosis. FAPs with aberrant activation of STAT3-IL-6 signalling were also found in mouse models of spinal cord injury, spinal muscular atrophy, amyotrophic lateral sclerosis (ALS) and in muscles of ALS patients. Inactivation of STAT3-IL-6 signalling in FAPs effectively countered muscle atrophy and fibrosis in mouse models of acute denervation and ALS (SOD mice). Activation of pathogenic FAPs following loss of integrity of neuromuscular junctions further illustrates the functional versatility of FAPs in response to homeostatic perturbations and suggests their potential contribution to the pathogenesis of neuromuscular diseases. 10.1038/s41556-018-0151-y
    mTORC1 and PKB/Akt control the muscle response to denervation by regulating autophagy and HDAC4. Castets Perrine,Rion Nathalie,Théodore Marine,Falcetta Denis,Lin Shuo,Reischl Markus,Wild Franziska,Guérard Laurent,Eickhorst Christopher,Brockhoff Marielle,Guridi Maitea,Ibebunjo Chikwendu,Cruz Joseph,Sinnreich Michael,Rudolf Rüdiger,Glass David J,Rüegg Markus A Nature communications Loss of innervation of skeletal muscle is a determinant event in several muscle diseases. Although several effectors have been identified, the pathways controlling the integrated muscle response to denervation remain largely unknown. Here, we demonstrate that PKB/Akt and mTORC1 play important roles in regulating muscle homeostasis and maintaining neuromuscular endplates after nerve injury. To allow dynamic changes in autophagy, mTORC1 activation must be tightly balanced following denervation. Acutely activating or inhibiting mTORC1 impairs autophagy regulation and alters homeostasis in denervated muscle. Importantly, PKB/Akt inhibition, conferred by sustained mTORC1 activation, abrogates denervation-induced synaptic remodeling and causes neuromuscular endplate degeneration. We establish that PKB/Akt activation promotes the nuclear import of HDAC4 and is thereby required for epigenetic changes and synaptic gene up-regulation upon denervation. Hence, our study unveils yet-unknown functions of PKB/Akt-mTORC1 signaling in the muscle response to nerve injury, with important implications for neuromuscular integrity in various pathological conditions. 10.1038/s41467-019-11227-4