Muscle biologies
Abstract
Muscular dystrophies are a group of genetic neuromuscular disorders that involve severe muscle wasting. Transforming growth factor β-activated kinase 1 (TAK1) is an important signaling protein that regulates cell survival, growth, and inflammation. TAK1 has been recently found to promote myofiber growth in the skeletal muscle of adult mice. However, the role of TAK1 in muscle diseases remains poorly understood. In the present study, we have investigated how TAK1 affects the progression of dystrophic phenotype in the mdx mouse model of Duchenne muscular dystrophy (DMD). TAK1 is highly activated in the dystrophic muscle of mdx mice during the peak necrotic phase. While targeted inducible inactivation of TAK1 inhibits myofiber injury in young mdx mice, it results in reduced muscle mass and contractile function. TAK1 inactivation also causes loss of muscle mass in adult mdx mice. By contrast, forced activation of TAK1 through overexpression of TAK1 and TAB1 induces myofiber growth without having any deleterious effect on muscle histopathology. Collectively, our results suggest that TAK1 is a positive regulator of skeletal muscle mass and targeted regulation of TAK1 can suppress myonecrosis and ameliorate disease progression in DMD.
Authors
Anirban Roy, Tatiana E. Koike, Aniket S. Joshi, Meiricris Tomaz da Silva, Kavya Mathukumalli, Mingfu Wu, Ashok Kumar
Abstract
Phosphoinositides (PI) are membrane lipids that regulate signal transduction and vesicular trafficking. X-linked centronuclear myopathy (XLCNM), also called myotubular myopathy, results from loss-of-function mutations in the Mtm1 gene, which encodes the myotubularin phosphatidylinositol 3-phosphate (PtdIns3P) lipid phosphatase. No therapy for this disease is currently available. Previous studies showed that loss of expression of the class II phosphoinositide 3-kinase (PI3K) PI3K-C2β protein improved the phenotypes of a XLCNM mouse model. PI3Ks are well known to have extensive scaffolding functions and the importance of the catalytic activity of this PI3K for rescue remains unclear. Here, using PI3K-C2β kinase-dead mice, we show that the selective inactivation of PI3K-C2β kinase activity is sufficient to fully prevent muscle atrophy and weakness, histopathology, and sarcomere and triad disorganization in Mtm1 knockout mice. This rescue correlates with normalization of PtdIns3P level and mTORC1 activity, a key regulator of protein synthesis and autophagy. Conversely, lack of PI3K-C2β kinase activity did not rescue the histopathology of the BIN1 autosomal centronuclear myopathy mouse model. Overall, these findings support the development of specific PI3K-C2β kinase inhibitors to cure myotubular myopathy.
Authors
Xènia Massana-Muñoz, Marie Goret, Vasugi Nattarayan, David Reiss, Christine Kretz, Gaetan Chicanne, Bernard Payrastre, Bart Vanhaesebroeck, Jocelyn Laporte
Abstract
Metabolic crosstalk from skeletal muscle to multiple organs is important for maintaining homeostasis, and its dysregulation can lead to various diseases. Chronic glucocorticoid administration often induces muscle atrophy and metabolic disorders such as diabetes and central obesity; however, the detailed underlying mechanism remains unclear. We previously reported that the deletion of glucocorticoid receptor (GR) in skeletal muscle increases muscle mass and reduces fat mass through muscle–liver–fat communication under physiological conditions. In this study, we show that muscle GR signaling plays a crucial role in accelerating obesity through the induction of hyperinsulinemia. Fat accumulation in liver and adipose tissue, muscle atrophy, hyperglycemia, and hyperinsulinemia induced by chronic corticosterone (CORT) treatment improved in muscle-specific GR knockout (GRmKO) mice. Such CORT-induced fat accumulation was alleviated by suppressing insulin production (streptozotocin injection), indicating that hyperinsulinemia enhanced by muscle GR signaling promotes obesity. Strikingly, glucose intolerance and obesity in ob/ob mice without CORT treatment were also improved in GRmKO mice, indicating that muscle GR signaling contributes to obesity-related metabolic changes, regardless of systemic glucocorticoid levels. Thus, this study provides new insight for the treatment of obesity and diabetes by targeting muscle GR signaling.
Authors
Hiroki Yamazaki, Masaaki Uehara, Noritada Yoshikawa, Akiko Kuribara-Souta, Motohisa Yamamoto, Yasuko Hirakawa, Yasuaki Kabe, Makoto Suematsu, Hirotoshi Tanaka
Abstract
Volumetric muscle loss (VML) is an acute trauma that results in persistent inflammation, supplantation of muscle tissue with fibrotic scarring, and decreased muscle function. The cell types, nature of cellular communication, and tissue locations that drive the aberrant VML response have remained elusive. Herein, we used spatial transcriptomics on a mouse model of VML and observed VML engenders a unique spatial pro-fibrotic pattern driven by crosstalk between fibrotic and inflammatory macrophages and mesenchymal derived cells. The dysregulated response impinged on muscle stem cell mediated repair, and targeting this circuit resulted in increased regeneration and reductions in inflammation and fibrosis. Collectively, these results enhance our understanding of the cellular crosstalk that drives aberrant regeneration and provides further insight into possible avenues for fibrotic therapy exploration.
Authors
Jacqueline A. Larouche, Emily C. Wallace, Bonnie D. Spence, Eric Buras, Carlos A. Aguilar
Abstract
Antisense oligonucleotide (AO)-mediated therapy is a promising strategy to treat several neurological diseases including spinal muscular atrophy (SMA). However, limited delivery to the central nervous system (CNS) with AOs administered intravenously or subcutaneously is a major challenge. Here we demonstrate a single subcutaneous administration of cell-penetrating peptide DG9 conjugated to an AO called phosphorodiamidate morpholino oligomers (PMOs) reaches the CNS and significantly prolonged the median survival compared to unconjugated PMO and R6G-PMO in a severe SMA mouse model. Treated mice exhibited significantly higher expression of full-length SMN2 expression (FL-SMN2) in both the CNS and systemic tissues compared to non-treated and unmodified AO-treated mice. The treatment ameliorated the atrophic musculature and improved breathing function accompanied by improved muscle strength and innervation at the neuromuscular junction with no signs of apparent toxicity. We also demonstrated DG9-conjugated PMO localizes in nuclei in the spinal cord and brain after subcutaneous injections. Our data identify DG9 peptide conjugation as a powerful way to improve the efficacy of AO-mediated splice modulation. Finally, DG9-PMO is a promising therapeutic option to treat SMA and other neurological diseases, overcoming the necessity for intrathecal injections and treating body-wide tissues without apparent toxicity.
Authors
Tejal Aslesh, Esra Erkut, Jun Ren, Kenji Rowel Q. Lim, Stanley Woo, Susan Hatlevig, Hong M. Moulton, Simon Gosgnach, John Greer, Rika Maruyama, Toshifumi Yokota
Abstract
The muscular dystrophies (MDs) are genetic muscle diseases that result in progressive muscle degeneration followed by the fibrotic replacement of affected muscles as regenerative processes fail. Therapeutics that specifically address the fibrosis and failed regeneration associated with MDs represent a major unmet clinical need for MD patients, particularly those with advanced-stage disease progression. The current study investigated targeting NAD(P)H oxidase 4 (NOX4) as a potential strategy to reduce fibrosis and promote regeneration in disease-burdened muscle that models Duchenne muscular dystrophy (DMD). NOX4 was elevated in the muscles of dystrophic mice and DMD patients, localizing primarily to interstitial cells located between muscle fibers. Genetic and pharmacological targeting of NOX4 significantly reduced fibrosis in dystrophic respiratory and limb muscles. Mechanistically, NOX4 targeting decreased the number of fibrosis-depositing cells (myofibroblasts) and restored the number of muscle-specific stem cells (satellite cells) localized to their physiological niche, thereby rejuvenating muscle regeneration. Furthermore, acute inhibition of NOX4 was sufficient to induce apoptotic clearing of myofibroblasts within dystrophic muscle. These data indicate that targeting NOX4 is an effective strategy to promote the beneficial remodeling of disease-burdened muscle representative of DMD and, potentially, other MDs and muscle pathologies.
Authors
David W. Hammers
Abstract
Gene mutations causing loss of dystrophin result in the severe muscle disease known as Duchenne muscular dystrophy (DMD). Despite efforts at genetic repair, DMD therapy remains largely palliative. Loss of dystrophin destabilizes the sarcolemmal membrane impacting mechanosensitive cation channels to increase calcium entry, promoting cell damage, and eventually muscle dysfunction. One putative channel is transient receptor potential canonical 6 (TRPC6) that we showed contributes to abnormal force and calcium stress-responses in mouse cardiomyocytes lacking dystrophin and haplodeficient in utrophin mdx/utrn+/- (HET). Here, we show in both HET and the far more severe homozygous mdx/utrn-/- (DKO) mouse that TRPC6 gene deletion or its selective pharmacologic inhibition (BI 749327) prolongs survival 2-3-fold, improving skeletal and cardiac muscle and bone defects. Gene pathways reduced by BI 749327 treatment most prominently regulate fat metabolism and TGFβ1 signaling. These results support the testing of TRPC6 inhibitors in human trials for other diseases as a novel DMD therapy.
Authors
Brian L. Lin, Joseph Y. Shin, William P.D. Jeffreys, Nadan Wang, Clarisse A. Lukban, Megan C. Moorer, Esteban Velarde, Olivia A. Hanselman, Seoyoung Kwon, Suraj Kannan, Ryan C. Riddle, Christopher W. Ward, Steven S. Pullen, Antonio Filareto, David A. Kass
Abstract
Mineralocorticoid receptor (MR) antagonists (MRAs) slow cardiomyopathy in Duchenne Muscular Dystrophy (DMD) patients and improve skeletal muscle pathology and function in dystrophic mice. However, glucocorticoids, known anti-inflammatory drugs, remain standard-of-care for DMD, despite substantial side effects. Exact mechanisms underlying MR signaling contribution to dystrophy are unknown. Whether MRAs affect inflammation in dystrophic muscles and how they compare to glucocorticoids is unclear. The MRA spironolactone and glucocorticoid prednisolone were each administered for one week to dystrophic mdx mice during peak skeletal muscle necrosis to compare effects on inflammation. Both drugs reduced cytokine levels in mdx quadriceps, but prednisolone elevated diaphragm cytokines. Spironolactone did not alter myeloid populations in mdx quadriceps or diaphragms, but prednisolone increased F4/80Hi macrophages. Both spironolactone and prednisolone reduced inflammatory gene expression in myeloid cells sorted from mdx quadriceps, while prednisolone additionally perturbed cell cycle genes. Spironolactone also repressed myeloid expression of the gene encoding fibronectin, while prednisolone increased its expression. Overall, spironolactone exhibits anti-inflammatory properties without altering leukocyte distribution within skeletal muscles while prednisolone suppresses quadriceps cytokines, but increases diaphragm cytokines and pathology. Anti-inflammatory properties of MRAs and different limb and respiratory muscle responses to glucocorticoids should be considered when optimizing treatments for DMD patients.
Authors
Zachary M. Howard, Chetan K. Gomatam, Charles P. Rabolli, Jeovanna Lowe, Arden B. Piepho, Shyam S. Bansal, Federica Accornero, Jill A. Rafael-Fortney
Abstract
BACKGROUND. During ageing there is a functional decline in the pool of muscle stem cells (MuSCs) which influences the functional and regenerative capacity of skeletal muscle. Preclinical evidence have suggested that Nicotinamide Riboside (NR) and Pterostilbene (PT) can improve muscle regeneration e.g. by increasing MuSC function. The objective of the present study was to investigate if NRPT-supplementation promotes skeletal muscle regeneration after muscle injury in elderly humans by improved recruitment of MuSCs. METHODS. 32 elderly men and women (55-80 yr) were randomized to daily supplementation with either NRPT (1000 mg NR + 200 mg PT) or matched placebo. Two weeks after initiation of supplementation, a skeletal muscle injury was induced by electrically-induced eccentric muscle work. Skeletal muscle biopsies were obtained pre, 2h, 2, 8, and 30 days post injury. RESULTS. A substantial skeletal muscle injury was induced by the protocol and associated with release of myoglobin and creatine kinase, muscle soreness, tissue edema, and a decrease in muscle strength. MuSC content, proliferation and cell size revealed a large demand for recruitment post injury but was not affected by NRPT. Furthermore, histological analyses of muscle fiber area, internal nuclei and embryonic Myosin Heavy Chain showed no effect of NRPT supplementation. CONCLUSION. Daily supplementation with 1000 mg NR+200 mg PT is safe but does not improve recruitment of the MuSC pool or other measures of muscle recovery in response to injury or subsequent regeneration in elderly subjects. TRIAL REGISTRATION. NCT03754842. FUNDING. Novo Nordisk Foundation (Ref. NNF17OC0027242) given to JTT and NJ. JTT, ED, SC, MVD, KT, and TM are supported by the Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR). CBMR is an independent Research Center at the University of Copenhagen that is partially funded by an unrestricted donation from the Novo Nordisk Foundation (NNF18CC0034900).
Authors
Jonas Brorson Jensen, Ole Lindgård Dollerup, Andreas Buch Møller, Tine B. Billeskov, Emilie Dalbram, Sabina Chubanava, Mads V. Damgaard, Ryan W. Dellinger, Kajetan Trošt, Thomas Moritz, Steffen Ringgaard, Niels Møller, Jonas T. Treebak, Jean Farup, Niels Jessen
Abstract
The sarcoplasmic reticulum (SR) plays an important role in calcium homeostasis. SR calcium mishandling is described in pathological conditions such as myopathies. Here, we investigated whether the nuclear receptor subfamily 1 group D member (NR1D1, also called REV-ERBα) regulates skeletal muscle SR calcium homeostasis. Our data demonstrate that NR1D1 deficiency in mice impairs SERCA-dependent SR calcium uptake. NR1D1 acts on calcium homeostasis by repressing the SERCA inhibitor myoregulin through direct binding to its promoter. Restoration of myoregulin counteracts the effects of NR1D1 overexpression on SR calcium content. Interestingly, myoblasts from Duchenne myopathy patients display lower NR1D1 expression, whereas pharmacological NR1D1 activation ameliorates SR calcium homeostasis, and improves muscle structure and function in dystrophic mdx/Utr+/- mice. Our findings demonstrate that NR1D1 regulates muscle SR calcium homeostasis, pointing to its therapeutic interest for mitigating myopathy.
Authors
Alexis Boulinguiez, Christian Duhem, Alicia Mayeuf-Louchart, Benoit Pourcet, Yasmine Sebti, Kateryna Kondratska, Valérie Montel, Stéphane Delhaye, Quentin Thorel, Justine Beauchamp, Aurore Hebras, Marion Gimenez, Marie Couvelaere, Mathilde Zecchin, Lise Ferri, Natalia Prevarskaya, Anne Forand, Christel Gentil, Jessica Ohana, France Piétri-Rouxel, Bruno Bastide, Bart Staels, Helene Duez, Steve Lancel
No posts were found with this tag.
