Alteration of Sarcoplasmic ReticulumCa2+Release in Skeletal Muscle from Calpain 3-Deficient Mice

Mutations ofCa2+-activated proteases (calpains) cause muscular dystrophies. Nevertheless, the specific role of calpains inCa2+signalling during the onset of dystrophies remains unclear. We investigatedCa2+handling in skeletal cells from calpain 3-deficient mice.[Ca2+]iresponses to caffeine, a ryanodine receptor (RyR) agonist, were decreased in −/− myotubes and absent in −/− myoblasts. The −/− myotubes displayed smaller amplitudes of theCa2+transients induced by cyclopiazonic acid in comparison to wild type cells. Inhibition of L-typeCa2+channels (LCC) suppressed the caffeine-induced[Ca2+]iresponses in −/− myotubes. Hence, the absence of calpain 3 modifies the sarcoplasmic reticulum (SR)Ca2+release, by a decrease of the SR content, an impairment of RyR signalling, and an increase of LCC activity. We propose that calpain 3-dependent proteolysis plays a role in activating support proteins of intracellularCa2+signalling at a stage of cellular differentiation which is crucial for skeletal muscle regeneration.

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Urokinase-dependent plasminogen activation is required for efficient skeletal muscle regeneration in vivo

Blood ◽

10.1182/blood.v97.6.1703 ◽

2001 ◽

Vol 97 (6) ◽

pp. 1703-1711 ◽

Cited By ~ 82

Author(s):

Frederic Lluı́s ◽

Josep Roma ◽

Mònica Suelves ◽

Maribel Parra ◽

Gloria Aniorte ◽

...

Keyword(s):

Skeletal Muscle ◽

Plasminogen Activator ◽

Muscle Regeneration ◽

Plasminogen Activators ◽

Skeletal Muscle Regeneration ◽

Plasminogen Activation ◽

Wild Type ◽

Type Plasminogen Activator ◽

Deficient Mice

Plasminogen activators urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) are extracellular proteases involved in various tissue remodeling processes. A requirement for uPA activity in skeletal myogenesis was recently demonstrated in vitro. The role of plasminogen activators in skeletal muscle regeneration in vivo in wild-type, uPA-deficient, and tPA-deficient mice is investigated here. Wild-type and tPA−/− mice completely repaired experimentally damaged skeletal muscle. In contrast, uPA−/− mice had a severe regeneration defect, with decreased recruitment of blood-derived monocytes to the site of injury and with persistent myotube degeneration. In addition, uPA-deficient mice accumulated fibrin in the degenerating muscle fibers; however, the defibrinogenation of uPA-deficient mice resulted in a correction of the muscle regeneration defect. A similar severe regeneration deficit with persistent fibrin deposition was also reproducible in plasminogen-deficient mice after injury, suggesting that fibrinolysis by uPA-mediated plasminogen activation plays a fundamental role in skeletal muscle regeneration. In conclusion, the uPA-plasmin system is identified as a critical component of the mammalian skeletal muscle regeneration process, possibly because it prevents intramuscular fibrin accumulation and contributes to the adequate inflammatory response after injury. These studies demonstrate the requirement of an extracellular proteolytic cascade during muscle regeneration in vivo.

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Plasmin activity is required for myogenesis in vitro and skeletal muscle regeneration in vivo

Blood ◽

10.1182/blood.v99.8.2835 ◽

2002 ◽

Vol 99 (8) ◽

pp. 2835-2844 ◽

Cited By ~ 62

Author(s):

Mònica Suelves ◽

Roser López-Alemany ◽

Frederic Lluı́s ◽

Gloria Aniorte ◽

Erika Serrano ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Regeneration ◽

Myoblast Fusion ◽

Skeletal Muscle Regeneration ◽

Wild Type ◽

Plasmin Activity ◽

Type Plasminogen Activator ◽

Deficient Mice

Abstract Plasmin, the primary fibrinolytic enzyme, has a broad substrate spectrum and is implicated in biologic processes dependent upon proteolytic activity, such as tissue remodeling and cell migration. Active plasmin is generated from proteolytic cleavage of the zymogen plasminogen (Plg) by urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA). Here, we have investigated the role of plasmin in C2C12 myoblast fusion and differentiation in vitro, as well as in skeletal muscle regeneration in vivo, in wild-type and Plg-deficient mice. Wild-type mice completely repaired experimentally damaged skeletal muscle. In contrast, Plg−/− mice presented a severe regeneration defect with decreased recruitment of blood-derived monocytes and lymphocytes to the site of injury and persistent myotube degeneration. In addition, Plg-deficient mice accumulated fibrin in the degenerating muscle fibers; however, fibrinogen depletion of Plg-deficient mice resulted in a correction of the muscular regeneration defect. Because we found that uPA, but not tPA, was induced in skeletal muscle regeneration, and persistent fibrin deposition was also reproducible in uPA-deficient mice following injury, we propose that fibrinolysis by uPA-dependent plasmin activity plays a fundamental role in skeletal muscle regeneration. In summary, we identify plasmin as a critical component of the mammalian skeletal muscle regeneration process, possibly by preventing intramuscular fibrin accumulation and by contributing to the adequate inflammatory response after injury. Finally, we found that inhibition of plasmin activity with α2-antiplasmin resulted in decreased myoblast fusion and differentiation in vitro. Altogether, these studies demonstrate the requirement of plasmin during myogenesis in vitro and muscle regeneration in vivo.

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Macrophages in Skeletal Muscle Dystrophies, An Entangled Partner

Journal of Neuromuscular Diseases ◽

10.3233/jnd-210737 ◽

2021 ◽

pp. 1-23

Author(s):

Theret Marine ◽

Saclier Marielle ◽

Messina Graziella ◽

Rossi M.V. Fabio

Keyword(s):

Skeletal Muscle ◽

Endothelial Cells ◽

Muscle Regeneration ◽

Genetic Diseases ◽

Fatty Infiltration ◽

Skeletal Muscle Regeneration ◽

Muscular Dystrophies ◽

Pathogenic Role ◽

Muscle Remodeling

While skeletal muscle remodeling happens throughout life, diseases that result in its dysfunction are accountable for many deaths. Indeed, skeletal muscle is exceptionally capable to respond to stimuli modifying its homeostasis, such as in atrophy, hypertrophy, regeneration and repair. In particular conditions such as genetic diseases (muscular dystrophies), skeletal muscle’s capacity to remodel is strongly affected and undergoes continuous cycles of chronic damage. This induces scarring, fatty infiltration, as well as loss of contractibility and of the ability to generate force. In this context, inflammation, primarily mediated by macrophages, plays a central pathogenic role. Macrophages contribute as the primary regulators of inflammation during skeletal muscle regeneration, affecting tissue-resident cells such as myogenic cells and endothelial cells, but also fibro-adipogenic progenitors, which are the main source of the fibro fatty scar. During skeletal muscle regeneration their function is tightly orchestrated, while in dystrophies their fate is strongly disturbed, resulting in chronic inflammation. In this review, we will discuss the latest findings on the role of macrophages in skeletal muscle diseases, and how they are regulated.

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A role of tensin in skeletal-muscle regeneration

Biochemical Journal ◽

10.1042/bj3560737 ◽

2001 ◽

Vol 356 (3) ◽

pp. 737-745 ◽

Cited By ~ 12

Author(s):

Akiko ISHII ◽

S. Hao LO

Keyword(s):

Skeletal Muscle ◽

Knockout Mice ◽

Muscle Regeneration ◽

Fold Increase ◽

Skeletal Muscle Regeneration ◽

Muscle Fibres ◽

Double Labelling ◽

Wild Type ◽

Associated Proteins

Regeneration of skeletal muscle requires the activation, proliferation, differentiation and fusion of satellite cells to generate new muscle fibres. This study was designed to determine the role of tensin in this process. Cardiotoxin was used to induce regeneration in the anterior tibial muscles of tensin-knockout and wild-type mice. From histological analysis, we found that the regeneration process lasted longer in knockout than in wild-type mice. To investigate the mechanism involved in this delay, we examined each regeneration step in animals and cultured primary cells. We found fewer proliferating myogenic cells identified by bromodeoxyuridine and desmin double labelling in knockout mice on the first 2 days after injury. Expression of myosin, paxillin, dystrophin and dystrophin-associated proteins were delayed in knockout mice. Withdrawal from the cell cycle was less efficient in isolated knockout myoblasts, and the fusion capacity was reduced in these cells as well. These defects in regeneration most likely contributed to the 9-fold increase of centrally nucleated fibres occurring in the non-injected knockout mice. Our results demonstrated clearly that tensin plays a role in skeletal-muscle regeneration.

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The Role of Metabolic Remodeling in Macrophage Polarization and Its Effect on Skeletal Muscle Regeneration

Antioxidants and Redox Signaling ◽

10.1089/ars.2017.7420 ◽

2019 ◽

Vol 30 (12) ◽

pp. 1553-1598 ◽

Cited By ~ 10

Author(s):

Francesca De Santa ◽

Laura Vitiello ◽

Alessio Torcinaro ◽

Elisabetta Ferraro

Keyword(s):

Skeletal Muscle ◽

Muscle Regeneration ◽

Macrophage Polarization ◽

Skeletal Muscle Regeneration ◽

Metabolic Remodeling

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The Potential Role of Insulin-Like Growth Factors in Skeletal Muscle Regeneration

Canadian Journal of Applied Physiology ◽

10.1139/h96-021 ◽

1996 ◽

Vol 21 (4) ◽

pp. 236-250 ◽

Cited By ~ 19

Author(s):

Jamie MacGregor ◽

Wade S. Parkhouse

Keyword(s):

Skeletal Muscle ◽

Growth Hormone ◽

Growth Factors ◽

Muscle Regeneration ◽

Potential Role ◽

Tissue Growth ◽

Skeletal Muscle Regeneration ◽

Tissue Type ◽

Insulin Like Growth Factors

The role of the insulin-like growth factors I and II (IGF-I and IGF-II), previously known as the somatomedins, in general growth and development of various tissues has been known for many years. Thought of exclusively as endocrine factors produced by the liver, and under the control of growth hormone, the somatomedins were known as the intermediaries by which growth hormone exerted its cellular effects during tissue growth and maturation. Eventually it was discovered that virtually every tissue type is capable of autocrine production of the IGFs, and their involvement in skeletal muscle tissue repair and regeneration became apparent. Recent advances in technology have allowed the characterisation of many of the different growth factors believed to play a role in muscle regeneration, and experimental manipulations of cells in culture have provided insight into the effects of the various growth factors on the myoblast. This paper explores the potential role of the IGFs in skeletal muscle regeneration. A critical role of IGF-II in terminal differentiation of proliferating muscle precurser cells following injury is proposed. Key words: growth factors, myogenesis, skeletal muscle regeneration

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Skeletal muscle reperfusion injury is mediated by neutrophils and the complement membrane attack complex

AJP Cell Physiology ◽

10.1152/ajpcell.1999.277.6.c1263 ◽

1999 ◽

Vol 277 (6) ◽

pp. C1263-C1268 ◽

Cited By ~ 60

Author(s):

Constantinos Kyriakides ◽

William Austen ◽

Yong Wang ◽

Joanne Favuzza ◽

Lester Kobzik ◽

...

Keyword(s):

Skeletal Muscle ◽

Reperfusion Injury ◽

Membrane Attack Complex ◽

Wild Type ◽

Complement Components ◽

Neutrophil Activity ◽

Deficient Mice ◽

Terminal Complement

The relative inflammatory roles of neutrophils, selectins, and terminal complement components are investigated in this study of skeletal muscle reperfusion injury. Mice underwent 2 h of hindlimb ischemia followed by 3 h of reperfusion. The role of neutrophils was defined by immunodepletion, which reduced injury by 38%, as did anti-selectin therapy with recombinant soluble P-selectin glycoprotein ligand-immunoglobulin (Ig) fusion protein. Injury in C5-deficient and soluble complement receptor type 1-treated wild-type mice was 48% less than that of untreated wild-type animals. Injury was restored in C5-deficient mice reconstituted with wild-type serum, indicating the effector role of C5–9. Neutropenic C5-deficient animals showed additive reduction in injuries (71%), which was lower than C5-deficient neutrophil-replete mice, indicating neutrophil activity without C5a. Hindlimb histological injury was worse in ischemic wild-type and C5-deficient animals reconstituted with wild-type serum. In conclusion, the membrane attack complex and neutrophils act additively to mediate skeletal muscle reperfusion injury. Neutrophil activity is independent of C5a but is dependent on selectin-mediated adhesion.

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