Exercise promotes α7 integrin gene transcription and protection of skeletal muscle

Abstract

Boppart MD, Volker SE, Alexander N, Burkin DJ, Kaufman SJ. Exercise promotes ␣7 integrin gene transcription and protection of skeletal muscle. Am J Physiol Regul Integr Comp Physiol 295: R1623-R1630, 2008. First published September 10, 2008 doi:10.1152/ajpregu.00089.2008.-The ␣7␤1 integrin is increased in skeletal muscle in response to injury-producing exercise, and transgenic overexpression of this integrin in mice protects against exerciseinduced muscle damage. The present study investigates whether the increase in the ␣7␤1 integrin observed in wild-type mice in response to exercise is due to transcriptional regulation and examines whether mobilization of the integrin at the myotendinous junction (MTJ) is a key determinant in its protection against damage. A single bout of downhill running exercise selectively increased transcription of the ␣7 integrin gene in 5-wk-old wild-type mice 3 h postexercise, and an increased ␣7 chain was detected in muscle sarcolemma adjacent to tendinous tissue immediately following exercise. The ␣7B, but not ␣7A isoform, was found concentrated and colocalized with tenascin-C in muscle fibers lining the MTJ. To further validate the importance of the integrin in the protection against muscle damage following exercise, muscle injury was quantified in ␣7 Ϫ/Ϫ mice. Muscle damage was extensive in ␣7 Ϫ/Ϫ mice in response to both a single and repeated bouts of exercise and was largely restricted to areas of high MTJ concentration and high mechanical force near the Achilles tendon. These results suggest that exercise-induced muscle injury selectively increases transcription of the ␣7 integrin gene and promotes a rapid change in the ␣7␤ integrin at the MTJ. These combined molecular and cellular alterations are likely responsible for integrin-mediated attenuation of exercise-induced muscle damage. exercise; injury; repeated bout effect; tenascin-C SEVERAL CLASSES OF CELL ADHESION molecules provide mechanisms for attaching cells to each other and to their extracellular environment. These include integrins, cadherins, and members of the immunoglobulin and selectin families (23). Integrins are transmembrane heterodimers of noncovalently bound ␣-and ␤-subunits. Integrins bind to specific ligands in the extracellular matrix, form clusters, and recruit cytoskeletal and cytoplasmic proteins that stabilize the cell and provide a means for communication between the outside and inside of the cell. Eighteen ␣-subunits and 8 ␤-subunits have been characterized, and at least 24 heterodimers have been identified (46).␣7␤1 is the predominant integrin in adult skeletal muscle. The ␣7 subunit determines the specificity of ligand binding to laminin in the basal lamina surrounding individual muscle fibers, whereas the ␤1 subunit participates in linkage with actin via several subsarcolemmal proteins, including ␣-actinin, talin, vinculin, paxillin, and tensin. Several other integrin ␣-subunits are expressed in skeletal muscle in association with ␤1, including ␣1, ␣3, ␣4, ␣5, ␣6, ␣9, ␣10, ␣11, and ␣v (15,29,30,39,...

Laminin-111 protein therapy prevents muscle disease in the mdx mouse model for Duchenne muscular dystrophy

“…Several genes have been shown to compensate for the loss of dystrophin and rescue dystrophic mice, including ␣ 7 ␤ 1 -integrin (11,18). Studies demonstrate that ␣ 7 ␤ 1 -integrin contributes to the structural and functional integrity of skeletal muscle (18)(19)(20). Because ␣ 7 ␤ 1 -integrin is expressed ubiquitously in skeletal and cardiac muscles, small molecule-based or protein-based approaches that target the expression of this gene hold significant promise for the treatment of DMD.…”

“…with 1 mg/kg laminin-111 or PBS. At 5 weeks of age, mice were placed on a Simplex II treadmill (Columbus Instruments) and completed a single downhill running exercise protocol using a modification of previously reported procedures (Ϫ12°, 15 m/min, 25-30 min) (19). The speed was gradually increased from 10 to 15 m/min during a 2-min warm-up period.…”

Transgenic overexpression of the α7 integrin reduces muscle pathology and improves viability in the dyW mouse model of merosin-deficient congenital muscular dystrophy type 1A

“…These mice were bred with dy W+/-animals to generate dy W-/-;itga7+ mice. Pups were genotyped at 10 days of age for the laminin-2 mutant and wild-type alleles and the Itga7 transgene, as previously described (Kuang et al, 1998;Burkin et al, 2005;Boppart et al, 2008).…”

Mesenchymal stem cells contribute to vascular growth in skeletal muscle in response to eccentric exercise

“…damage, and reductions in force following eccentric exercise (3,4,13). Our recently published work also suggests ␣ 7BX2 -integrin overexpression (MCK:␣ 7BX2 ; ␣ 7 Tg) can increase myogenesis, hypertrophic signaling, myofibrillar content, fiber cross-sectional area, muscle cross-sectional area, and maximal isometric force following single or multiple bouts of eccentric exercise (13,34), a type of exercise that results in muscle lengthening during load and ultrastructural damage in the form of sarcomere disruption and sarcolemma damage (23).…”