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      Effects of ursolic acid on sub-lesional muscle pathology in a contusion model of spinal cord injury

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          Abstract

          Spinal Cord Injury (SCI) results in severe sub-lesional muscle atrophy and fiber type transformation from slow oxidative to fast glycolytic, both contributing to functional deficits and maladaptive metabolic profiles. Therapeutic countermeasures have had limited success and muscle-related pathology remains a clinical priority. mTOR signaling is known to play a critical role in skeletal muscle growth and metabolism, and signal integration of anabolic and catabolic pathways. Recent studies show that the natural compound ursolic acid (UA) enhances mTOR signaling intermediates, independently inhibiting atrophy and inducing hypertrophy. Here, we examine the effects of UA treatment on sub-lesional muscle mTOR signaling, catabolic genes, and functional deficits following severe SCI in mice. We observe that UA treatment significantly attenuates SCI induced decreases in activated forms of mTOR, and signaling intermediates PI3K, AKT, and S6K, and the upregulation of catabolic genes including FOXO1, MAFbx, MURF-1, and PSMD11. In addition, UA treatment improves SCI induced deficits in body and sub-lesional muscle mass, as well as functional outcomes related to muscle function, motor coordination, and strength. These findings provide evidence that UA treatment may be a potential therapeutic strategy to improve muscle-specific pathological consequences of SCI.

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          IKKbeta/NF-kappaB activation causes severe muscle wasting in mice.

          Dongsheng Cai, J Daniel Frantz, Nicholas Tawa … (2004)
          Muscle wasting accompanies aging and pathological conditions ranging from cancer, cachexia, and diabetes to denervation and immobilization. We show that activation of NF-kappaB, through muscle-specific transgenic expression of activated IkappaB kinase beta (MIKK), causes profound muscle wasting that resembles clinical cachexia. In contrast, no overt phenotype was seen upon muscle-specific inhibition of NF-kappaB through expression of IkappaBalpha superrepressor (MISR). Muscle loss was due to accelerated protein breakdown through ubiquitin-dependent proteolysis. Expression of the E3 ligase MuRF1, a mediator of muscle atrophy, was increased in MIKK mice. Pharmacological or genetic inhibition of the IKKbeta/NF-kappaB/MuRF1 pathway reversed muscle atrophy. Denervation- and tumor-induced muscle loss were substantially reduced and survival rates improved by NF-kappaB inhibition in MISR mice, consistent with a critical role for NF-kappaB in the pathology of muscle wasting and establishing it as an important clinical target for the treatment of muscle atrophy.
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            Double muscling in cattle due to mutations in the myostatin gene.

            A. McPherron, S Lee (1997)
            Myostatin (GDF-8) is a member of the transforming growth factor beta superfamily of secreted growth and differentiation factors that is essential for proper regulation of skeletal muscle mass in mice. Here we report the myostatin sequences of nine other vertebrate species and the identification of mutations in the coding sequence of bovine myostatin in two breeds of double-muscled cattle, Belgian Blue and Piedmontese, which are known to have an increase in muscle mass relative to conventional cattle. The Belgian Blue myostatin sequence contains an 11-nucleotide deletion in the third exon which causes a frameshift that eliminates virtually all of the mature, active region of the molecule. The Piedmontese myostatin sequence contains a missense mutation in exon 3, resulting in a substitution of tyrosine for an invariant cysteine in the mature region of the protein. The similarity in phenotypes of double-muscled cattle and myostatin null mice suggests that myostatin performs the same biological function in these two species and is a potentially useful target for genetic manipulation in other farm animals.
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              Skeletal muscle hypertrophy and atrophy signaling pathways.

              David J Glass (2005)
              Skeletal muscle hypertrophy is defined as an increase in muscle mass, which in the adult animal comes as a result of an increase in the size, as opposed to the number, of pre-existing skeletal muscle fibers. The protein growth factor insulin-like growth factor 1 (IGF-1) has been demonstrated to be sufficient to induce skeletal muscle hypertrophy. Over the past few years, signaling pathways which are activated by IGF-1, and which are responsible for regulating protein synthesis pathways, have been defined. More recently, it has been show that IGF-1 can also block the transcriptional upregulation of key mediators of skeletal muscle atrophy, the ubiquitin-ligases MuRF1 and MAFbx (also called Atrogin-1). Further, it has been demonstrated recently that activation of the NF-kappaB transcription pathway, activated by cachectic factors such as TNFalpha, is sufficient to induce skeletal muscle atrophy, and this atrophy occurs in part via NF-kappaB-mediated upregulation of MuRF1. Further work has demonstrated a trigger for MAFbx expression upon treatment with TNFalpha--the p38 MAPK pathway. This review will focus on the recent progress in the understanding of molecular signalling, which governs skeletal muscle atrophy and hypertrophy, and the known instances of cross-regulation between the two systems.
              Article 0 comments Cited 257 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Gregory E. Bigford:
                ORCID: http://orcid.org/0000-0001-8990-3465
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – original draft
                Andrew J. Darr: Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – review & editing
                Valerie C. Bracchi-Ricard: Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – review & editing
                Han Gao: Role: InvestigationRole: Methodology
                Mark S. Nash: Role: Funding acquisitionRole: SupervisionRole: Writing – review & editing
                John R. Bethea: Role: Funding acquisitionRole: SupervisionRole: Writing – review & editing
                Andrew Philp: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 29 August 2018
                Publication date Collection: 2018
                Volume: 13
                Issue: 8
                Electronic Location Identifier: e0203042
                Affiliations
                [1 ] The Miami Project to Cure Paralysis, Miami, Florida, United States of America
                [2 ] Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida, United States of America
                [3 ] Department of Health Sciences Education, University of Illinois College of Medicine at Peoria, Peoria, Illinois, United States of America
                [4 ] Department of Biology, Drexel University, Philadelphia, Pennsylvania, United States of America
                [5 ] Department of Rehabilitation Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States of America
                Garvan Institute of Medical Research, AUSTRALIA
                Author notes

                Competing Interests: The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

                Author information
                http://orcid.org/0000-0001-8990-3465
                Article
                Publisher ID: PONE-D-18-08776
                DOI: 10.1371/journal.pone.0203042
                PMC ID: 6114926
                PubMed ID: 30157245
                SO-VID: 90e9b3dc-9898-4d18-bd1d-e3b716230be5
                Copyright © © 2018 Bigford et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 22 March 2018
                Date accepted : 14 August 2018
                Page count
                Figures: 4, Tables: 1, Pages: 20
                Funding
                Funded by: The Miami Project to Cure Paralysis
                This work was supported by the Miami Project to Cure Paralysis. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Musculoskeletal System
                Subject: Muscles
                Subject: Skeletal Muscles
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Musculoskeletal System
                Subject: Muscles
                Subject: Skeletal Muscles
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Musculoskeletal System
                Subject: Muscles
                Subject: Soleus Muscles
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Musculoskeletal System
                Subject: Muscles
                Subject: Soleus Muscles
                Subject: Biology and Life Sciences
                Subject: Physiology
                Subject: Muscle Physiology
                Subject: Muscle Functions
                Subject: Medicine and Health Sciences
                Subject: Physiology
                Subject: Muscle Physiology
                Subject: Muscle Functions
                Subject: Medicine and Health Sciences
                Subject: Critical Care and Emergency Medicine
                Subject: Trauma Medicine
                Subject: Traumatic Injury
                Subject: Neurotrauma
                Subject: Spinal Cord Injury
                Subject: Medicine and Health Sciences
                Subject: Neurology
                Subject: Spinal Cord Injury
                Subject: Medicine and Health Sciences
                Subject: Diagnostic Medicine
                Subject: Signs and Symptoms
                Subject: Atrophy
                Subject: Medicine and Health Sciences
                Subject: Pathology and Laboratory Medicine
                Subject: Signs and Symptoms
                Subject: Atrophy
                Subject: Biology and life sciences
                Subject: Cell biology
                Subject: Signal transduction
                Subject: Cell signaling
                Subject: Signaling cascades
                Subject: AKT signaling cascade
                Subject: Research and Analysis Methods
                Subject: Bioassays and Physiological Analysis
                Subject: Muscle Analysis
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Signal Transduction
                Subject: Cell Signaling
                Subject: Signaling Cascades
                Subject: Protein Kinase Signaling Cascade
                Custom metadata
                Data Availability All relevant data are within the paper and its Supporting Information files.

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