␣ 7 ␤ 1 -Integrin regulates mechanotransduction and prevents skeletal muscle injury

Dept. of Cell and Developmental Biology, University of Illinois, Urbana, IL 61801, USA.
AJP Cell Physiology (Impact Factor: 3.78). 07/2006; 290(6):C1660-5. DOI: 10.1152/ajpcell.00317.2005
Source: PubMed


Alpha7beta1-integrin links laminin in the extracellular matrix with the cell cytoskeleton and therein mediates transduction of mechanical forces into chemical signals. Muscle contraction and stretching ex vivo result in activation of intracellular signaling molecules that are integral to postexercise injury responses. Because alpha7beta1-integrin stabilizes muscle and provides communication between the matrix and cytoskeleton, the role of this integrin in exercise-induced cell signaling and skeletal muscle damage was assessed in wild-type and transgenic mice overexpressing the alpha7BX2 chain. We report here that increasing alpha7beta1-integrin inhibits phosphorylation of molecules associated with muscle damage, including the mitogen-activated protein kinases (JNK, p38, and ERK), following downhill running. Likewise, activation of molecules associated with hypertrophy (AKT, mTOR, and p70(S6k)) was diminished in mice overexpressing integrin. While exercise resulted in Evans blue dye-positive fibers, an index of muscle damage, increased integrin protected mice from injury. Moreover, exercise leads to an increase in alpha7beta1 protein. These experiments provide the first evidence that alpha7beta1-integrin is a negative regulator of mechanotransduction in vivo and provides resistance to exercise-induced muscle damage.

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Available from: Marni D Boppart, Jun 04, 2014
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    • "Mice created to overexpress α7 integrin specifically in skeletal muscle (MCK-α7BX2), referred to as α7Tg mice, were produced and bred in-house [26]. Overexpression of α7 integrin BX2 subunit was determined by polymerase chain reaction (PCR) analysis (primers: MCK1, 5′-CAAGCTGCACGCCTGGGTCC-3′ and AATII, 5′-GGCACCCATGACGTCCAGATTGAAG-3′) as previously described [27]. "
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    ABSTRACT: Introduction Mesenchymal stem cells (MSCs) reside in a variety of tissues and provide a stromal role in regulating progenitor cell function. Current studies focus on identifying the specific factors in the niche that can alter the MSC secretome, ultimately determining the effectiveness and timing of tissue repair. The purpose of the present study was to evaluate the extent to which substrate and mechanical strain simultaneously regulate MSC quantity, gene expression, and secretome. Methods MSCs (Sca-1+CD45-) isolated from murine skeletal muscle (muscle-derived MSCs, or mMSCs) via fluorescence-activated cell sorting were seeded onto laminin (LAM)- or collagen type 1 (COL)-coated membranes and exposed to a single bout of mechanical strain (10%, 1 Hz, 5 hours). Results mMSC proliferation was not directly affected by substrate or strain; however, gene expression of growth and inflammatory factors and extracellular matrix (ECM) proteins was downregulated in mMSCs grown on COL in a manner independent of strain. Focal adhesion kinase (FAK) may be involved in substrate regulation of mMSC secretome as FAK phosphorylation was significantly elevated 24 hours post-strain in mMSCs plated on LAM but not COL (P <0.05). Conditioned media (CM) from mMSCs exposed to both LAM and strain increased myoblast quantity 5.6-fold 24 hours post-treatment compared with myoblasts treated with serum-free media (P <0.05). This response was delayed in myoblasts treated with CM from mMSCs grown on COL. Conclusions Here, we demonstrate that exposure to COL, the primary ECM component associated with tissue fibrosis, downregulates genes associated with growth and inflammation in mMSCs and delays the ability for mMSCs to stimulate myoblast proliferation.
    Stem Cell Research & Therapy 06/2014; 5(3):74. DOI:10.1186/scrt463 · 3.37 Impact Factor
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    • "The α7β1 integrin is a transmembrane heterodimeric protein that can link laminin in the extracellular matrix to the myoblast and myotube cytoskeleton for the purposes of cellular signaling, migration and adhesion (Crawley et al., 1997). We have previously demonstrated that a single 30 min bout of eccentric exercise can result in injury and upregulate transcription and protein expression of the α7 integrin subunit at 24 h post-exercise (Boppart et al., 2006, 2008). We subsequently determined that transgenic expression of the α7 integrin under a muscle-specific promoter (MCK:α7B integrin; α7Tg) can prevent eccentric exercise-associated damage and macrophage infiltration, while paradoxically stimulating a rapid increase in satellite cell number and new fiber synthesis (Lueders et al., 2011). "
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    ABSTRACT: Skeletal muscle repair is essential for effective remodeling, tissue maintenance, and initiation of beneficial adaptations post-eccentric exercise. A series of well characterized events, such as recruitment of immune cells and activation of satellite cells, constitute the basis for muscle regeneration. However, details regarding the fine-tuned regulation of this process in response to different types of injury are open for investigation. Muscle-resident non-myogenic, non-satellite stem cells expressing conventional mesenchymal stem cell (MSC) markers, have the potential to significantly contribute to regeneration given the role for bone marrow-derived MSCs in whole body tissue repair in response to injury and disease. The purpose of this mini-review is to highlight a regulatory role for Pnon-satellite stem cells in the process of skeletal muscle healing post-eccentric exercise. The non-myogenic, non-satellite stem cell fraction will be defined, its role in tissue repair will be briefly reviewed, and recent studies demonstrating a contribution to eccentric exercise-induced regeneration will be presented.
    Frontiers in Physiology 11/2013; 4:310. DOI:10.3389/fphys.2013.00310 · 3.53 Impact Factor
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    • "The α7β1 integrin is enriched in specialized areas of skeletal muscle [24]–[26] and its importance in muscle is clearly evident in humans and murine models that progressively develop myopathy when the α7 integrin gene is mutated or the protein is not present [27], [28]. We have previously reported that α7 integrin RNA and total protein increase in response to eccentric exercise in the form of downhill running, and muscle-specific transgenic expression of the α7BX2 integrin protects against exercise-induced muscle damage [29], [30]. Our most recent results suggest that macrophage accumulation is markedly suppressed and maximal isometric force is preserved in α7 integrin transgenic mice (α7Tg) following exercise, likely contributing to a phenotype of enhanced growth, including new fiber synthesis and marked fiber hypertrophy [31], [32]. "
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    ABSTRACT: Eccentric, or lengthening, contractions result in injury and subsequently stimulate the activation and proliferation of satellite stem cells which are important for skeletal muscle regeneration. The discovery of alternative myogenic progenitors in skeletal muscle raises the question as to whether stem cells other than satellite cells accumulate in muscle in response to exercise and contribute to post-exercise repair and/or growth. In this study, stem cell antigen-1 (Sca-1) positive, non-hematopoetic (CD45⁻) cells were evaluated in wild type (WT) and α7 integrin transgenic (α7Tg) mouse muscle, which is resistant to injury yet liable to strain, 24 hr following a single bout of eccentric exercise. Sca-1⁺CD45⁻ stem cells were increased 2-fold in WT muscle post-exercise. The α7 integrin regulated the presence of Sca-1⁺ cells, with expansion occurring in α7Tg muscle and minimal cells present in muscle lacking the α7 integrin. Sca-1⁺CD45⁻ cells isolated from α7Tg muscle following exercise were characterized as mesenchymal-like stem cells (mMSCs), predominantly pericytes. In vitro multiaxial strain upregulated mMSC stem cells markers in the presence of laminin, but not gelatin, identifying a potential mechanistic basis for the accumulation of these cells in muscle following exercise. Transplantation of DiI-labeled mMSCs into WT muscle increased Pax7⁺ cells and facilitated formation of eMHC⁺DiI⁻ fibers. This study provides the first demonstration that mMSCs rapidly appear in skeletal muscle in an α7 integrin dependent manner post-exercise, revealing an early event that may be necessary for effective repair and/or growth following exercise. The results from this study also support a role for the α7 integrin and/or mMSCs in molecular- and cellular-based therapeutic strategies that can effectively combat disuse muscle atrophy.
    PLoS ONE 01/2012; 7(1):e29760. DOI:10.1371/journal.pone.0029760 · 3.23 Impact Factor
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