Information

Why is wound contraction very slow?


I am working on mathematical model for healing of dermal wounds. For anyone who's a bit familiar with Physics and Math, for the model I use the Cauchy Momentum Equation as a basis, and from there I use already established literature to expand to a so-called morphoelastic model.

From a physical perspective, if a force is exerted, you would expect a material to start moving, upon which stresses arise, until a new balance is found. This all usually happens on a timescale of second. Now when wound healing is regarded, the contraction force is exerted by fibroblasts. I have read that wound contraction happens at a speed of up to 0.75/mm per day. On the one hand this is impressive, yet on the other hand it is very slow when viewed from the mechanical perspective.

So my question is: Is there a biological effect or phenomenon that slows down? Could it be that the migration speed of fibroblasts is the bottle neck? Or maybe skin is in some way tethered to underlying tissue? I know very little about biology, so any help would be appreciated!

Thanks in advance


Short Answer : You can not pinpoint any single step for this delay. It is a combination of multiple processes.

Long Answer : I think there are multiple factors that can contribute to this. Dermal Wound healing is a multi-step and complex process typically includes inflammation, new tissue formation and remodeling (Gurtner et al 2008). Each of these stages involved very complex signaling pathways of various components. In addition, there are multiple types of fibroblast cells involved in this process. You are most likely talking about Myofibroblasts who bring the edges of a wound together. However, this itself is a very complex process involving interaction with the proliferation and migration of both mesenchymal and epithelial cells. This is further tightly controlled by Keratinocyte-fibroblast interactions (Werner et al 2007).

So what can you do? : The the physical analogy, which you are trying to implement here, has to apply within some assumptions. You can declare some fitting parameter(s) which can contribute to all the process and validate it according to good experimental data, probably with some kind of mutant data where the wound healing process is slowed down or accelerated. While deciding your assumptions, use as fewer assumptions as possible else you will end up creating Spherical Cow.


Tissue Injury and Aging

Tissues of all types are vulnerable to injury and, inevitably, aging. In the former case, understanding how tissues respond to damage can guide strategies to aid repair. In the latter case, understanding the impact of aging can help in the search for ways to diminish its effects.

Tissue Injury and Repair

Inflammation is the standard, initial response of the body to injury. Whether biological, chemical, physical, or radiation burns, all injuries lead to the same sequence of physiological events. Inflammation limits the extent of injury, partially or fully eliminates the cause of injury, and initiates repair and regeneration of damaged tissue. Necrosis, or accidental cell death, causes inflammation. Apoptosis is programmed cell death, a normal step-by-step process that destroys cells no longer needed by the body. By mechanisms still under investigation, apoptosis does not initiate the inflammatory response. Acute inflammation resolves over time by the healing of tissue. If inflammation persists, it becomes chronic and leads to diseased conditions. Arthritis and tuberculosis are examples of chronic inflammation. The suffix “-itis” denotes inflammation of a specific organ or type, for example, peritonitis is the inflammation of the peritoneum, and meningitis refers to the inflammation of the meninges, the tough membranes that surround the central nervous system

The four cardinal signs of inflammation—redness, swelling, pain, and local heat—were first recorded in antiquity. Cornelius Celsus is credited with documenting these signs during the days of the Roman Empire, as early as the first century AD. A fifth sign, loss of function, may also accompany inflammation.

Upon tissue injury, damaged cells release inflammatory chemical signals that evoke local vasodilation, the widening of the blood vessels. Increased blood flow results in apparent redness and heat. In response to injury, mast cells present in tissue degranulate, releasing the potent vasodilator histamine. Increased blood flow and inflammatory mediators recruit white blood cells to the site of inflammation. The endothelium lining the local blood vessel becomes “leaky” under the influence of histamine and other inflammatory mediators allowing neutrophils, macrophages, and fluid to move from the blood into the interstitial tissue spaces. The excess liquid in tissue causes swelling, more properly called edema. The swollen tissues squeezing pain receptors cause the sensation of pain. Prostaglandins released from injured cells also activate pain neurons. Non-steroidal anti-inflammatory drugs (NSAIDs) reduce pain because they inhibit the synthesis of prostaglandins. High levels of NSAIDs reduce inflammation. Antihistamines decrease allergies by blocking histamine receptors and as a result the histamine response.

After containment of an injury, the tissue repair phase starts with removal of toxins and waste products. Clotting (coagulation) reduces blood loss from damaged blood vessels and forms a network of fibrin proteins that trap blood cells and bind the edges of the wound together. A scab forms when the clot dries, reducing the risk of infection. Sometimes a mixture of dead leukocytes and fluid called pus accumulates in the wound. As healing progresses, fibroblasts from the surrounding connective tissues replace the collagen and extracellular material lost by the injury. Angiogenesis, the growth of new blood vessels, results in vascularization of the new tissue known as granulation tissue. The clot retracts pulling the edges of the wound together, and it slowly dissolves as the tissue is repaired. When a large amount of granulation tissue forms and capillaries disappear, a pale scar is often visible in the healed area. A primary union describes the healing of a wound where the edges are close together. When there is a gaping wound, it takes longer to refill the area with cells and collagen. The process called secondary union occurs as the edges of the wound are pulled together by what is called wound contraction. When a wound is more than one quarter of an inch deep, sutures (stitches) are recommended to promote a primary union and avoid the formation of a disfiguring scar. Regeneration is the addition of new cells of the same type as the ones that were injured ([link]).

Watch this video to see a hand heal. Over what period of time do you think these images were taken?

Tissue and Aging

According to poet Ralph Waldo Emerson, “The surest poison is time.” In fact, biology confirms that many functions of the body decline with age. All the cells, tissues, and organs are affected by senescence, with noticeable variability between individuals owing to different genetic makeup and lifestyles. The outward signs of aging are easily recognizable. The skin and other tissues become thinner and drier, reducing their elasticity, contributing to wrinkles and high blood pressure. Hair turns gray because follicles produce less melanin, the brown pigment of hair and the iris of the eye. The face looks flabby because elastic and collagen fibers decrease in connective tissue and muscle tone is lost. Glasses and hearing aids may become parts of life as the senses slowly deteriorate, all due to reduced elasticity. Overall height decreases as the bones lose calcium and other minerals. With age, fluid decreases in the fibrous cartilage disks intercalated between the vertebrae in the spine. Joints lose cartilage and stiffen. Many tissues, including those in muscles, lose mass through a process called atrophy. Lumps and rigidity become more widespread. As a consequence, the passageways, blood vessels, and airways become more rigid. The brain and spinal cord lose mass. Nerves do not transmit impulses with the same speed and frequency as in the past. Some loss of thought clarity and memory can accompany aging. More severe problems are not necessarily associated with the aging process and may be symptoms of underlying illness.

As exterior signs of aging increase, so do the interior signs, which are not as noticeable. The incidence of heart diseases, respiratory syndromes, and type 2 diabetes increases with age, though these are not necessarily age-dependent effects. Wound healing is slower in the elderly, accompanied by a higher frequency of infection as the capacity of the immune system to fend off pathogen declines.

Aging is also apparent at the cellular level because all cells experience changes with aging. Telomeres, regions of the chromosomes necessary for cell division, shorten each time cells divide. As they do, cells are less able to divide and regenerate. Because of alterations in cell membranes, transport of oxygen and nutrients into the cell and removal of carbon dioxide and waste products from the cell are not as efficient in the elderly. Cells may begin to function abnormally, which may lead to diseases associated with aging, including arthritis, memory issues, and some cancers.

The progressive impact of aging on the body varies considerably among individuals, but Studies indicate, however, that exercise and healthy lifestyle choices can slow down the deterioration of the body that comes with old age.

Tissues and Cancer Cancer is a generic term for many diseases in which cells escape regulatory signals. Uncontrolled growth, invasion into adjacent tissues, and colonization of other organs, if not treated early enough, are its hallmarks. Health suffers when tumors “rob” blood supply from the “normal” organs.

A mutation is defined as a permanent change in the DNA of a cell. Epigenetic modifications, changes that do not affect the code of the DNA but alter how the DNA is decoded, are also known to generate abnormal cells. Alterations in the genetic material may be caused by environmental agents, infectious agents, or errors in the replication of DNA that accumulate with age. Many mutations do not cause any noticeable change in the functions of a cell. However, if the modification affects key proteins that have an impact on the cell’s ability to proliferate in an orderly fashion, the cell starts to divide abnormally. As changes in cells accumulate, they lose their ability to form regular tissues. A tumor, a mass of cells displaying abnormal architecture, forms in the tissue. Many tumors are benign, meaning they do not metastasize nor cause disease. A tumor becomes malignant, or cancerous, when it breaches the confines of its tissue, promotes angiogenesis, attracts the growth of capillaries, and metastasizes to other organs ([link]). The specific names of cancers reflect the tissue of origin. Cancers derived from epithelial cells are referred to as carcinomas. Cancer in myeloid tissue or blood cells form myelomas. Leukemias are cancers of white blood cells, whereas sarcomas derive from connective tissue. Cells in tumors differ both in structure and function. Some cells, called cancer stem cells, appear to be a subtype of cell responsible for uncontrolled growth. Recent research shows that contrary to what was previously assumed, tumors are not disorganized masses of cells, but have their own structures.

Watch this video to learn more about tumors. What is a tumor?

Cancer treatments vary depending on the disease’s type and stage. Traditional approaches, including surgery, radiation, chemotherapy, and hormonal therapy, aim to remove or kill rapidly dividing cancer cells, but these strategies have their limitations. Depending on a tumor’s location, for example, cancer surgeons may be unable to remove it. Radiation and chemotherapy are difficult, and it is often impossible to target only the cancer cells. The treatments inevitably destroy healthy tissue as well. To address this, researchers are working on pharmaceuticals that can target specific proteins implicated in cancer-associated molecular pathways.

Chapter Review

Inflammation is the classic response of the body to injury and follows a common sequence of events. The area is red, feels warm to the touch, swells, and is painful. Injured cells, mast cells, and resident macrophages release chemical signals that cause vasodilation and fluid leakage in the surrounding tissue. The repair phase includes blood clotting, followed by regeneration of tissue as fibroblasts deposit collagen. Some tissues regenerate more readily than others. Epithelial and connective tissues replace damaged or dead cells from a supply of adult stem cells. Muscle and nervous tissues undergo either slow regeneration or do not repair at all.

Age affects all the tissues and organs of the body. Damaged cells do not regenerate as rapidly as in younger people. Perception of sensation and effectiveness of response are lost in the nervous system. Muscles atrophy, and bones lose mass and become brittle. Collagen decreases in some connective tissue, and joints stiffen.

Interactive Link Questions

Watch this video to see a hand heal. Over what period of time do you think these images were taken?


Carbohydrate-Based Therapeutics

Snigdha Mishra , . Vinod K. Tiwari , in Studies in Natural Products Chemistry , 2016

Cardiac Glycosides as Therapeutics

Cardiac glycosides acts on contractile force of cardiac muscles that can interfere in functioning of heart and hence acts as toxic agents. Some of them have been recommended for treatment of uncontrolled heart conditions after purification and modification. Ouabain (159) ( Fig. 10.43 ), is a cardiac glycoside extracted from ripe seeds of Strophanthus gratus and bark of Acokanthera ouabaio, used in biological studies of cell in order to inhibit Na-K (+)-exchanging ATPase [143] . Digoxin (160) is a purified cardiac glycoside found in the foxglove plant, Digitalis lanata, conventionally used for the treatment of heart conditions like atrial fibrillation and atrial flutter that cannot be controlled by medication and lead to severe conditions like heart failure. Cardiac glycosides inhibits Na + /K + ATPase in cardiac myocytes resulting in intracellular increase in sodium ion concentration that triggers intracellular Ca + accumulation facilitating release of calcium ions by sarcoplasmic reticulum in heart, which eventually increases contractility [144] .

Figure 10.42 . Triazolyl glycohybrid-based β-glucosidase inhibitors.

Figure 10.43 . Cardiac glycosides.

Recently, we have utilized click chemistry for an easy access of morpholine-fused triazoles starting from sugar alkynes [145] . Reaction proceeds via azido alcohols, which after propargylation and metal-free cyclization affords morpholine-fused triazoles of chemotherapeutic potential. Furthermore, the azido alcohols have successfully been utilized for the synthesis of bis-triazolyl ethisterone glycoconjugates ( Fig. 10.44 ) [146] .

Figure 10.44 . bis-triazolyl ethisterone glycoconjugates.


Introduction

In Greek mythology, the Rod of Asclepius is a serpent-entwined rod wielded by the Greek god Asclepius. Wounded patients could be healed if they were brought to the temple and the serpent licked their wounds during the night (Gardner, 1925). The Rod of Asclepius is still used as a symbol associated with modern medicine and health care. Wound healing is a primary survival mechanism that is largely taken for granted. Although, wound healing has long been considered a primary aspect of medical practice, disturbed wound healing is infrequently discussed in the literature, and there is no acceptable classification to describe wound healing processes in the oral region.

Wound healing entails a sequence of complex biological processes (Bielefeld et al., 2013). All tissues follow an essentially identical pattern to promote healing with minimal scar formation. One fundamental difference between would healing and regeneration is that all tissues are capable of renewal, but healed tissue does not always possess the same functionality or morphology as the lost tissue (Takeo et al., 2015). Moreover, wound healing is a protective function of the body that focuses on quick recovery (Wong et al., 2013), whereas the process of regeneration in an hostile environment takes more time. In particular, the oral cavity is a remarkable environment in which wound healing occurs in warm oral fluid that contains millions of microorganisms.

The present review provides a basic overview of wound healing, focusing on specific characteristics of the process of wound healing in the oral cavity. We also discuss local and general factors that play roles in achieving efficient wound healing.


References

Brown, R. A., Prajapati, R., McGrouther, D. A., Yannas, I. V. & Eastwood, M. Tensional homeostasis in dermal fibroblasts: mechanical responses to mechanical loading in three-dimensional substrates. J. Cell Physiol. 175, 323–332 (1998).Describes the first evidence that fibroblasts respond cytomechanically to externally applied mechanical loads that maintain a set level of pre-stress in their matrix, which is termed tensional homeostasis.

Muellner, T. et al. Light and electron microscopic study of stress-shielding effects on rat patellar tendon. Arch. Orthop. Trauma Surg. 121, 561–565 (2001).

Brown, R. A. in Future Strategies for Tissue and Organ Replacement (eds Polak, J. M., Hench, L. L. & Kemp, P.) 51–78 (World Scientific Publishing, Singapore, 2002).

Eastwood, M., Mudera, V. C., McGrouther, D. A. & Brown, R. A. Effect of precise mechanical loading on fibroblast populated collagen lattices: morphological changes. Cell Motil. Cytoskeleton 40, 13–21 (1998).

Serini, G. & Gabbiani, G. Mechanisms of myofibroblast activity and phenotypic modulation. Exp. Cell Res. 250, 273–283 (1999).

Powell, D. W. et al. Myofibroblasts. I. Paracrine cells important in health and disease. Am. J. Physiol. 277, C1–C9 (1999).

Grinnell, F. Fibroblast-collagen-matrix contraction: growth-factor signalling and mechanical loading. Trends Cell Biol. 10, 362–365 (2000).Describes fibroblast collagen matrix-contraction models and recent evidence that indicates that the state of cellular mechanical loading determines the mechanism that cells use to regulate contraction.

Carrel, A. & Hartmann, A. Cicatrization of wounds. I. The relation between the size and the rate of its cicatrization. J. Exp. Med. 24, 429–450 (1916).

Payling Wright, G. An Introduction to Pathology 2nd Edition (Longmans Green and Co., London, 1954).

Abercrombie, M., Flint, M. H. & James, D. W. Wound contraction in relation to collagen formation in scorbutic guinea pigs. J. Embryol. Exp. Morph. 4, 167 (1956).

Gabbiani, G., Ryan, G. B. & Majno, G. Presence of modified fibroblasts in granulation tissue and their possible role in wound contraction. Experientia 27, 549–550 (1971).

Walker, G. A., Guerrero, I. A. & Leinwand, L. A. Myofibroblasts: molecular crossdressers. Curr. Top. Dev. Biol. 51, 91–107 (2001).

Darby, I., Skalli, O. & Gabbiani, G. α-smooth muscle actin is transiently expressed by myofibroblasts during experimental wound healing. Lab. Invest. 63, 21–29 (1990).

Skalli, O. et al. A monoclonal antibody against α-smooth muscle actin: a new probe for smooth muscle differentiation. J. Cell Biol. 103, 2787–2796 (1986).The specific antibody for α-SM actin shows that this protein is expressed temporarily in granulation-tissue fibroblasts.

Desmouliere, A., Geinoz, A., Gabbiani, F. & Gabbiani, G. Transforming growth factor-β1 induces α-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J. Cell Biol. 122, 103–111 (1993).The first demonstration that TGF-β1 is involved in the induction of α-SM actin in normal fibroblasts and myofibroblasts.

Burridge, K. & Chrzanowska-Wodnicka, M. Focal adhesions, contractility, and signaling. Annu. Rev. Cell Dev. Biol. 12, 463–518 (1996).

Kreis, T. E. & Birchmeier, W. Stress fiber sarcomeres of fibroblasts are contractile. Cell 22, 555–561 (1980).

Dugina, V., Fontao, L., Chaponnier, C., Vasiliev, J. & Gabbiani, G. Focal adhesion features during myofibroblastic differentiation are controlled by intracellular and extracellular factors. J. Cell Sci. 114, 3285–3296 (2001).Demonstration that focal adhesion size and composition are modulated by intracellular and extracellular factors that regulate the myofibroblast phenotype.

Singer, I. I., Kawka, D. W., Kazazis, D. M. & Clark, R. A. In vivo co-distribution of fibronectin and actin fibers in granulation tissue: immunofluorescence and electron microscope studies of the fibronexus at the myofibroblast surface. J. Cell Biol. 98, 2091–2106 (1984).

Chicurel, M. E., Chen, C. S. & Ingber, D. E. Cellular control lies in the balance of forces. Curr. Opin. Cell Biol. 10, 232–239 (1998).

Geiger, B. & Bershadsky, A. Assembly and mechanosensory function of focal contacts. Curr. Opin. Cell Biol. 13, 584–592 (2001).

Gabbiani, G., Chaponnier, C. & Huttner, I. Cytoplasmic filaments and gap junctions in epithelial cells and myofibroblasts during wound healing. J. Cell Biol. 76, 561–568 (1978).

Spanakis, S. G., Petridou, S. & Masur, S. K. Functional gap junctions in corneal fibroblasts and myofibroblasts. Invest. Ophthalmol. Vis. Sci. 39, 1320–1328 (1998).

Jamieson, S., Going, J. J., D'Arcy, R. & George, W. D. Expression of gap junction proteins connexin 26 and connexin 43 in normal human breast and in breast tumours. J. Pathol. 184, 37–43 (1998).

Harris, A. K., Stopak, D. & Wild, P. Fibroblast traction as a mechanism for collagen morphogenesis. Nature 290, 249–251 (1981).

Grinnell, F. Fibroblasts, myofibroblasts, and wound contraction. J. Cell Biol. 124, 401–404 (1994).

Bell, E., Ivarsson, B. & Merrill, C. Production of a tissue-like structure by contraction of collagen lattices by human fibroblasts of different proliferative potential in vitro. Proc. Natl Acad. Sci. USA 76, 1274–1278 (1979).

Ehrlich, H. P. & Rajaratnam, J. B. Cell locomotion forces versus cell contraction forces for collagen lattice contraction: an in vitro model of wound contraction. Tissue Cell 22, 407–417 (1990).

Hinz, B., Mastrangelo, D., Iselin, C. E., Chaponnier, C. & Gabbiani, G. Mechanical tension controls granulation tissue contractile activity and myofibroblast differentiation. Am. J. Pathol. 159, 1009–1020 (2001).This paper showed that the myofibroblastic phenotype is regulated by mechanical tension in vivo.

Gross, J., Farinelli, W., Sadow, P., Anderson, R. & Bruns, R. On the mechanism of skin wound 'contraction': a granulation tissue 'knockout' with a normal phenotype. Proc. Natl Acad. Sci. USA 92, 5982–5986 (1995).

Berry, D. P., Harding, K. G., Stanton, M. R., Jasani, B. & Ehrlich, H. P. Human wound contraction: collagen organization, fibroblasts, and myofibroblasts. Plast. Reconstr. Surg. 102, 124–131 (1998).

Kapanci, Y., Ribaux, C., Chaponnier, C. & Gabbiani, G. Cytoskeletal features of alveolar myofibroblasts and pericytes in normal human and rat lung. J. Histochem. Cytochem. 40, 1955–1963 (1992).

Lindahl, P. & Betsholtz, C. Not all myofibroblasts are alike: revisiting the role of PDGF-A and PDGF-B using PDGF-targeted mice. Curr. Opin. Nephrol. Hypertens. 7, 21–26 (1998).

Martin, P. Wound healing — aiming for perfect skin regeneration. Science 276, 75–81 (1997).

Lindahl, P., Johansson, B. R., Leveen, P. & Betsholtz, C. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277, 242–245 (1997).

Bostrom, H. et al. PDGF-A signaling is a critical event in lung alveolar myofibroblast development and alveogenesis. Cell 85, 863–873 (1996).

Desmouliere, A., Rubbia-Brandt, L., Grau, G. & Gabbiani, G. Heparin induces α-smooth muscle actin expression in cultured fibroblasts and in granulation tissue myofibroblasts. Lab. Invest. 67, 716–726 (1992).

Rubbia-Brandt, L., Sappino, A. P. & Gabbiani, G. Locally applied GM-CSF induces the accumulation of α-smooth muscle actin containing myofibroblasts. Virchows Arch. B Cell Pathol. Incl. Mol. Pathol. 60, 73–82 (1991).

Ffrench-Constant, C., Van de Water, L., Dvorak, H. F. & Hynes, R. O. Reappearance of an embryonic pattern of fibronectin splicing during wound healing in the adult rat. J. Cell Biol. 109, 903–914 (1989).

Serini, G. et al. The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growth factor- β1. J. Cell Biol. 142, 873–881 (1998).Shows that the ED-A domain of cellular fibronectin is required for α-SM actin stimulating activity of TGF-β1.

Burridge, K. Are stress fibres contractile? Nature 294, 691–692 (1981).

Pelham, R. J. Jr & Wang, Y. Cell locomotion and focal adhesions are regulated by substrate flexibility. Proc. Natl Acad. Sci. USA 94, 13661–13665 (1997).This paper shows the ability of cells to survey the mechanical properties of their surrounding environment, and the effect this has on focal adhesion formation. This indicates the possible involvement of both protein tyrosine phosphorylation and myosin-generated cortical forces in this process.

Tomasek, J. J., Haaksma, C. J., Eddy, R. J. & Vaughan, M. B. Fibroblast contraction occurs on release of tension in attached collagen lattices: dependency on an organized actin cytoskeleton and serum. Anat. Rec. 232, 359–368 (1992).Shows that fibroblasts in stressed collagen lattices acquire the myofibroblast phenotype and that these cells can generate contractile force, which results in rapid contraction of the collagen lattices.

Elsdale, T. & Bard, J. Collagen substrata for studies on cell behavior. J. Cell Biol. 54, 626–637 (1972).

Mochitate, K., Pawelek, P. & Grinnell, F. Stress relaxation of contracted collagen gels: disruption of actin filament bundles, release of cell surface fibronectin, and down-regulation of DNA and protein synthesis. Exp. Cell Res. 193, 198–207 (1991).

Halliday, N. L. & Tomasek, J. J. Mechanical properties of the extracellular matrix influence fibronectin fibril assembly in vitro. Exp. Cell Res. 217, 109–117 (1995).

Porter, R. A., Brown, R. A., Eastwood, M., Occleston, N. L. & Khaw, P. T. Ultrastructural changes during contraction of collagen lattices by ocular fibroblasts. Wound Repair Regen. 6, 157–166 (1998).

Tomasek, J. J. et al. Gelatinase A activation is regulated by the organization of the polymerized actin cytoskeleton. J. Biol. Chem. 272, 7482–7487 (1997).

Kasugai, S. et al. Measurements of the isometric contractile forces generated by dog periodontal ligament fibroblasts in vitro. Arch. Oral Biol. 35, 597–601 (1990).

Delvoye, P., Wiliquet, P., Leveque, J. L., Nusgens, B. V. & Lapiere, C. M. Measurement of mechanical forces generated by skin fibroblasts embedded in a three-dimensional collagen gel. J. Invest. Dermatol. 97, 898–902 (1991).

Kolodney, M. S. & Wysolmerski, R. B. Isometric contraction by fibroblasts and endothelial cells in tissue culture: a quantitative study. J. Cell Biol. 117, 73–82 (1992).

Eastwood, M., McGrouther, D. A. & Brown, R. A. A culture force monitor for measurement of contraction forces generated in human dermal fibroblast cultures: evidence for cell-matrix mechanical signalling. Biochim. Biophys. Acta 1201, 186–192 (1994).

Chrzanowska-Wodnicka, M. & Burridge, K. Rho-stimulated contractility drives the formation of stress fibers and focal adhesions. J. Cell Biol. 133, 1403–1415 (1996).Shows that activated Rho stimulates contractility, drives the formation of stress fibres and focal adhesions, and elevates tyrosine phosphorylation.

Vaughan, M. B., Howard, E. W. & Tomasek, J. J. Transforming growth factor-β1 promotes the morphological and functional differentiation of the myofibroblast. Exp. Cell Res. 257, 180–189 (2000).Shows that TGF-β1 will promote the formation of stress fibres, focal adhesions and fibronectin fibrils by fibroblasts that are cultured in stressed collagen lattices, and that this correlates with increased generation of contractile force.

Ronnov-Jessen, L. & Petersen, O. W. Induction of α-smooth muscle actin by transforming growth factor-β1 in quiescent human breast gland fibroblasts. Implications for myofibroblast generation in breast neoplasia. Lab. Invest. 68, 696–707 (1993).

Roberts, A. B. & Sporn, M. B. in The Molecular and Cellular Biology of Wound Repair (ed. Clark, R. A. F.) 275–308 (Plenum Press, New York, 1996).

O'Kane, S. & Ferguson, M. W. Transforming growth factor-βs and wound healing. Int. J. Biochem. Cell Biol. 29, 63–78 (1997).

Massague, J. The transforming growth factor-β family. Annu. Rev. Cell Biol. 6, 597–641 (1990).

Border, W. A. & Noble, N. A. Transforming growth factorβ in tissue fibrosis. N. Engl. J. Med. 331, 1286–1292 (1994).

Schmid, P., Itin, P., Cherry, G., Bi, C. & Cox, D. A. Enhanced expression of transforming growth factor-β type I and type II receptors in wound granulation tissue and hypertrophic scar. Am. J. Pathol. 152, 485–493 (1998).

Kim, S. J. et al. Autoinduction of transforming growth factor β1 is mediated by the AP-1 complex. Mol. Cell. Biol. 10,1492–1497 (1990).

Yang, L. et al. Healing of burn wounds in transgenic mice overexpressing transforming growth factor-β1 in the epidermis. Am. J. Pathol. 159, 2147–2157 (2001).

Roberts, A. B. et al. Transforming growth factor type β: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc. Natl Acad. Sci. USA 83, 4167–4171 (1986).

Lund, L. R. et al. Transforming growth factor-β is a strong and fast acting positive regulator of the level of type-1 plasminogen activator inhibitor mRNA in WI-38 human lung fibroblasts. EMBO J. 6, 1281–1286 (1987).

Borsi, L., Castellani, P., Risso, A. M., Leprini, A. & Zardi, L. Transforming growth factor-β regulates the splicing pattern of fibronectin messenger RNA precursor. FEBS Lett. 261, 175–178 (1990).

Miyazono, K., Ichijo, H. & Heldin, C. H. Transforming growth factor-β: latent forms, binding proteins and receptors. Growth Factors 8, 11–22 (1993).

Khalil, N. TGF-β: from latent to active. Microbes Infect. 1, 1255–1263 (1999).

Massague, J. & Wotton, D. Transcriptional control by the TGF-β/Smad signaling system. EMBO J. 19, 1745–1754 (2000).

Heldin, C. H., Miyazono, K. & ten Dijke, P. TGF-β signalling from cell membrane to nucleus through SMAD proteins. Nature 390, 465–471 (1997).

Schnabl, B. et al. The role of Smad3 in mediating mouse hepatic stellate cell activation. Hepatology 34, 89–100 (2001).

Tomasek, J. J., Flanders, K. C. & Haaksma, C. J. Smad3 signaling is not required for TGF-β1 promoted myofibroblast differentiation. Wound Repair Regen. (in the press).

Hautmann, M. B., Madsen, C. S. & Owens, G. K. A transforming growth factor β (TGFβ) control element drives TGFβ-induced stimulation of smooth muscle α-actin gene expression in concert with two CArG elements. J. Biol. Chem. 272, 10948–10956 (1997).

Roy, S. G., Nozaki, Y. & Phan, S. H. Regulation of α-smooth muscle actin gene expression in myofibroblast differentiation from rat lung fibroblasts. Int. J. Biochem. Cell Biol. 33, 723–734 (2001).

Sullivan, K. M., Lorenz, H. P., Meuli, M., Lin, R. Y. & Adzick, N. S. A model of scarless human fetal wound repair is deficient in transforming growth factor β. J. Pediatr. Surg. 30, 198–202 (1995).

Mack, C. P. & Owens, G. K. Regulation of smooth muscle α-actin expression in vivo is dependent on CArG elements within the 5′ and first intron promoter regions. Circ. Res. 84, 852–861 (1999).

Swartz, E. A., Johnson, A. D. & Owens, G. K. Two MCAT elements of the SM α-actin promoter function differentially in SM versus non-SM cells. Am. J. Physiol. 275, C608–C618 (1998).

Schurch, W., Skalli, O. & Gabbiani, G. in Dupuytren's Disease (eds McFarlane, R., McGrouther, D. A. & Flint, M. H.) 31–47 (Churchill Livingston, Edinburgh, 1990).

Van der Loop, F. T., Gabbiani, G., Kohnen, G., Ramaekers, F. C. & van Eys, G. J. Differentiation of smooth muscle cells in human blood vessels as defined by smoothelin, a novel marker for the contractile phenotype. Arterioscler. Thromb. Vasc. Biol. 17, 665–671 (1997).

Christen, T. et al. Mechanisms of neointima formation and remodeling in the porcine coronary artery. Circulation 103, 882–888 (2001).

Van der Loop, F. T., Schaart, G., Timmer, E. D., Ramaekers, F. C. & van Eys, G. J. Smoothelin, a novel cytoskeletal protein specific for smooth muscle cells. J. Cell Biol. 134, 401–411 (1996).

Jones, R. C. & Jacobson, M. Angiogenesis in the hypertensive lung: response to ambient oxygen tension. Cell Tissue Res. 300, 263–284 (2000).

Higton, D. I. R. & James, D. W. The force of contraction of full-thickness wounds of rabbit skin. Br. J. Surg. 51, 462–466 (1964).

Majno, G., Gabbiani, G., Hirschel, B. J., Ryan, G. B. & Statkov, P. R. Contraction of granulation tissue in vitro: similarity to smooth muscle. Science 173, 548–550 (1971).

Gabbiani, G., Hirschel, B. J., Ryan, G. B., Statkov, P. R. & Majno, G. Granulation tissue as a contractile organ. A study of structure and function. J. Exp. Med. 135, 719–734 (1972).

Appleton, I., Tomlinson, A., Chander, C. L. & Willoughby, D. A. Effect of endothelin-1 on croton oil-induced granulation tissue in the rat. A pharmacologic and immunohistochemical study. Lab. Invest. 67, 703–710 (1992).

Hinz, B., Celetta, G., Tomasek, J. J., Gabbiani, G. & Chaponnier, C. α-smooth muscle actin expression upregulates fibroblast contractile activity. Mol. Biol. Cell 12, 2730–2741 (2001).This shows that a correlation exists between α-SM actin expression and contractile activity of fibroblast in vitro.

Arora, P. D. & McCulloch, C. A. Dependence of collagen remodelling on α-smooth muscle actin expression by fibroblasts. J. Cell Physiol. 159, 161–175 (1994).

Arora, P. D., Narani, N. & McCulloch, C. A. The compliance of collagen gels regulates transforming growth factor-β induction of α-smooth muscle actin in fibroblasts. Am. J. Pathol. 154, 871–882 (1999).Shows that TGF-β1-induced increases of α-SM actin content are dependent on the resistance of the substrate to deformation and that the generation of intracellular tension is a central determinant of contractile cytoskeletal gene expression.

Ronnov-Jessen, L. & Petersen, O. W. A function for filamentous α-smooth muscle actin: retardation of motility in fibroblasts. J. Cell Biol. 134, 67–80 (1996).

Chaponnier, C. et al. The specific NH2-terminal sequence Ac-EEED of α-smooth muscle actin plays a role in polymerization in vitro and in vivo. J. Cell Biol. 130, 887–895 (1995).

Hinz, B., Gabbiani, G. & Chaponnier, C. The N-terminal peptide of α-smooth muscle actin inhibits force generation by the myofibroblast in vitro and in vivo. J. Cell Biol. (in the press).This shows that the amino-terminal sequence of α-SM actin inhibits myofibroblast contraction in vitro and in vivo , which indicates a new therapeutic strategy.

Nobes, C. D. & Hall, A. Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. Cell 81, 53–62 (1995).

Balaban, N. Q. et al. Force and focal adhesion assembly: a close relationship studied using elastic micropatterned substrates. Nature Cell Biol. 3, 466–472 (2001).

Geiger, B., Bershadsky, A., Pankov, R. & Yamada, K. M. Transmembrane crosstalk between the extracellular matrix–cytoskeleton crosstalk. Nature Rev. Mol. Cell Biol. 2, 793–805 (2001).

Zamir, E. & Geiger, B. Molecular complexity and dynamics of cell-matrix adhesions. J. Cell Sci. 114, 3583–3590 (2001).

Cukierman, E., Pankov, R., Stevens, D. R. & Yamada, K. M. Taking cell-matrix adhesions to the third dimension. Science 294, 1708–1712 (2001).

Heino, J., Ignotz, R. A., Hemler, M. E., Crouse, C. & Massague, J. Regulation of cell adhesion receptors by transforming growth factor-β. Concomitant regulation of integrins that share a common β1 subunit. J. Biol. Chem. 264, 380–388 (1989).

Ignotz, R. A., Heino, J. & Massague, J. Regulation of cell adhesion receptors by transforming growth factor-β. Regulation of vitronectin receptor and LFA-1. J. Biol. Chem. 264, 389–392 (1989).

Brown, R. A. et al. Enhanced fibroblast contraction of 3D collagen lattices and integrin expression by TGF-β1 and β3: mechanoregulatory growth factors? Exp. Cell Res. 274, 310–322 (2002).Study shows very rapid stimulation of traction force by TGF-β1 and TGF-β3, which is consistent with activated cytoskeletal contraction.

Katoh, K., Kano, Y., Masuda, M., Onishi, H. & Fujiwara, K. Isolation and contraction of the stress fiber. Mol. Biol. Cell 9, 1919–1938 (1998).

Leung, T., Manser, E., Tan, L. & Lim, L. A novel serine/threonine kinase binding the Ras-related RhoA GTPase which translocates the kinase to peripheral membranes. J. Biol. Chem. 270, 29051–29054 (1995).

Ishizaki, T. et al. The small GTP-binding protein Rho binds to and activates a 160 kDa Ser/Thr protein kinase homologous to myotonic dystrophy kinase. EMBO J. 15, 1885–1893 (1996).

Chihara, K. et al. Cytoskeletal rearrangements and transcriptional activation of c-fos serum response element by Rho-kinase. J. Biol. Chem. 272, 25121–25127 (1997).

Amano, M. et al. Myosin II activation promotes neurite retraction during the action of Rho and Rho-kinase. Genes Cells 3, 177–188 (1998).

Amano, M. et al. Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase). J. Biol. Chem. 271, 20246–20249 (1996).

Kimura, K. et al. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science 273, 245–248 (1996).

Kawano, Y. et al. Phosphorylation of myosin-binding subunit (MBS) of myosin phosphatase by Rho-kinase in vivo. J. Cell Biol. 147, 1023–1038 (1999).

Katoh, K. et al. Rho-kinase-mediated contraction of isolated stress fibers. J. Cell Biol. 153, 569–584 (2001).Describes an isolated reactivatable stress fibre contraction model in which actomyosin-based nonmuscle contractility is regulated by two kinase systems: MLCK, which promotes rapid contraction, and Rho kinase, which maintains a sustained contraction.

Gong, M. C. et al. Role of guanine nucleotide-binding proteins–ras-family or trimeric proteins or both in Ca 2+ sensitization of smooth muscle. Proc. Natl Acad. Sci. USA 93, 1340–1345 (1996).

Tomasek, J. J., Martin, M. D., Vaughan, M. B., Cowan, R. & Kropp, B. P. Myofibroblast contraction in granulation tissue is dependent on Rho kinase. Mol. Biol. Cell 11, 88a (2000).

Parizi, M., Howard, E. W. & Tomasek, J. J. Regulation of LPA-promoted myofibroblast contraction: role of Rho, myosin light chain kinase, and myosin light chain phosphatase. Exp. Cell Res. 254, 210–220 (2000).Shows that LPA-promoted contraction of myofibroblasts occurs through the Rho–Rho kinase pathway, probably by inhibiting myosin light chain phosphatase.

Glimcher, M. J. in Pathobiology (eds Kang, A. H. & Nimni, M. E.) 137–165 (CRC Press, Boca Ratton, 1992).

Glimcher, M. J. & Peabody, H. M. in Dupuytren's Disease (eds McFarlane, R., McGrouther, D. A. & Flint, M. H.) 72–85 (Churchill Livingston, Edinburgh, 1990).

Ryan, G. B. et al. Myofibroblasts in human granulation tissue. Hum. Pathol. 5, 55–67 (1974).

Grinnell, F. & Ho, C. H. Transforming growth factorβ stimulates fibroblast–collagen matrix contraction by different mechanisms in mechanically loaded and unloaded matrices. Exp. Cell Res. 273, 248–255 (2002).

Brown, R. A. & Byers, P. D. Swelling of cartilage and expansion of the collagen network. Calcif. Tissue Int. 45, 260–261 (1989).

Nemetschek, T. et al. [Functional properties of parallel fibred connective tissue with special regard to viscoelasticity (author's transl)]. Virchows Arch. A Pathol. Anat. Histol. 386, 125–151 (1980).

Woessner, J. F. in Collagen in Health and Disease (eds Jayson, M. I. V. & Weiss, J. B.) 506–527 (Churchill Livingston, Edinburgh, 1982).

Byers, P. D. & Brown, R. A. in Methods in Cartilage Research (eds Maroudas, A. & Kuettner, K. E.) 318–321 (Academic, London, 1990).

Gabbiani, G., Le Lous, M., Bailey, A. J., Bazin, S. & Delaunay, A. Collagen and myofibroblasts of granulation tissue. A chemical, ultrastructural and immunologic study. Virchows Archiv. B Cell Pathol. 21, 133–145 (1976).

Graham, H. K., Holmes, D. F., Watson, R. B. & Kadler, K. E. Identification of collagen fibril fusion during vertebrate tendon morphogenesis. The process relies on unipolar fibrils and is regulated by collagen–proteoglycan interaction. J. Mol. Biol. 295, 891–902 (2000).

Danielson, K. G. et al. Targeted disruption of decorin leads to abnormal collagen fibril morphology and skin fragility. J. Cell Biol. 136, 729–743 (1997).

Kypreos, K. E., Birk, D., Trinkaus-Randall, V., Hartmann, D. J. & Sonenshein, G. E. Type V collagen regulates the assembly of collagen fibrils in cultures of bovine vascular smooth muscle cells. J. Cell Biochem. 80, 146–155 (2000).

Young, B. B., Gordon, M. K. & Birk, D. E. Expression of type XIV collagen in developing chicken tendons: association with assembly and growth of collagen fibrils. Dev. Dyn. 217, 430–439 (2000).

Watson, R. B., Holmes, D. F., Graham, H. K., Nusgens, B. V. & Kadler, K. E. Surface located procollagen N-propeptides on dermatosparactic collagen fibrils are not cleaved by procollagen N-proteinase and do not inhibit binding of decorin to the fibril surface. J. Mol. Biol. 278, 195–204 (1998).

Ezura, Y., Chakravarti, S., Oldberg, A., Chervoneva, I. & Birk, D. E. Differential expression of lumican and fibromodulin regulate collagen fibrillogenesis in developing mouse tendons. J. Cell Biol. 151, 779–788 (2000).

Prajapati, R. T., Chavally-Mis, B., Herbage, D., Eastwood, M. & Brown, R. A. Mechanical loading regulates protease production by fibroblasts in three-dimensional collagen substrates. Wound Repair Regen. 8, 226–237 (2000).

Desmouliere, A., Redard, M., Darby, I. & Gabbiani, G. Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. Am. J. Pathol. 146, 56–66 (1995).

Grinnell, F., Zhu, M., Carlson, M. A. & Abrams, J. M. Release of mechanical tension triggers apoptosis of human fibroblasts in a model of regressing granulation tissue. Exp. Cell Res. 248, 608–619 (1999).

Mudera, V. C. et al. Molecular responses of human dermal fibroblasts to dual cues: contact guidance and mechanical load. Cell Motil. Cytoskeleton 45, 1–9 (2000).

Wakatsuki, T., Kolodney, M. S., Zahalak, G. I. & Elson, E. L. Cell mechanics studied by a reconstituted model tissue. Biophys. J. 79, 2353–2368 (2000).

Schurch, W., Seemayer, T. A. & Gabbiani, G. in Histology for Pathologists (ed. Sternberg, S. S.) 129–165 (Raven Press, Ltd, New York, 1997).

Garana, R. M. et al. Radial keratotomy. II. Role of the myofibroblast in corneal wound contraction. Invest. Ophthalmol. Vis. Sci. 33, 3271–3282 (1992).

Jester, J. V., Petroll, W. M., Barry, P. A. & Cavanagh, H. D. Expression of α-smooth muscle (α-SM) actin during corneal stromal wound healing. Invest. Ophthalmol. Vis. Sci. 36, 809–819 (1995).

Jester, J. V. et al. Corneal keratocytes: in situ and in vitro organization of cytoskeletal contractile proteins. Invest. Ophthalmol. Vis. Sci. 35, 730–743 (1994).

Masur, S. K., Conors, R. J. Jr, Cheung, J. K. & Antohi, S. Matrix adhesion characteristics of corneal myofibroblasts. Invest. Ophthalmol. Vis. Sci. 40, 904–910 (1999).

Jester, J. V., Petroll, W. M. & Cavanagh, H. D. Corneal stromal wound healing in refractive surgery: the role of myofibroblasts. Prog. Retin. Eye Res. 18, 311–356 (1999).

Masur, S. K., Dewal, H. S., Dinh, T. T., Erenburg, I. & Petridou, S. Myofibroblasts differentiate from fibroblasts when plated at low density. Proc. Natl Acad. Sci. USA 93, 4219–4223 (1996).

Glasser, S. R. & Julian, J. Intermediate filament protein as a marker of uterine stromal cell decidualization. Biol. Reprod. 35, 463–474 (1986).

Toccanier-Pelte, M.-F., Skalli, O., Kapanci, Y. & Gabbiani, G. Characterization of stromal cells with myoid features in lymph nodes and spleen in normal and pathological conditions. Am. J. Pathol. 129, 109–118 (1987).

Sappino, A. P., Dietrich, P. Y., Skalli, O., Widgren, S. & Gabbiani, G. Colonic pericryptal fibroblasts. Differentiation pattern in embryogenesis and phenotypic modulation in epithelial proliferative lesions. Virchows Arch. A Pathol. Anat. Histopathol. 415, 551–557 (1989).

Kaye, G. I., Lane, N. & Pascal, P. R. Colonic pericryptal fibroblast sheath: replication, migration and cytodifferentiation of a mesenchymal cell-system in adult tissue. II. Fine structural aspects of normal rabbit and human colon. Gastroenterology 54, 852–865 (1968).

Czernobilsky, B. et al. α smooth muscle actin (α-SM actin) in normal human ovaries, in ovarian stromal hyperplasia and in ovarian neoplasms. Virchows Arch. B Cell Pathol. Incl. Mol. Pathol. 57, 55–61 (1989).

Beertsen, W., Everts, V. & van den Hooff, A. Fine structure of fibroblasts in the periodontal ligament of the rat incisor and their possible role in tooth eruption. Arch. Oral Biol. 19, 1087–1098 (1974).

Bressler, R. S. Myoid cells in the capsule of the adrenal gland and in monolayers derived from cultured adrenal capsules. Anat. Rec. 177, 525–531 (1973).

Yokoi, Y. et al. Immunocytochemical detection of desmin in fat-storing cells (Ito cells). Hepatology 4, 709–714 (1984).

Kapanci, Y., Ribaux, C., Chaponnier, C. & Gabbiani, G. Cytoskeletal features of alveolar myofibroblasts and pericytes in normal human and rat lung. J. Histochem. Cytochem. 40, 1955–1963 (1992).

Charbord, P. et al. The cytoskeleton of stromal cells from human bone marrow cultures resembles that of cultured smooth muscle cells. Exp. Hematol. 18, 276–282 (1990).


Example - Healing of Pre-Ulcer Dermatitis

One of the best uses of SRCPs would be the healing of pre-ulcer dermatitis before the damaged skin develops open sores. The photographs at left are an example of healing "at-risk" skin with pre-ulcer dermatitis. In the top photo, the patient has two open skin ulcers visible in left top and bottom of the photo. On the right of the photo, there are reddish fissures developing into skin ulcers. In the bottom photo, the application of a copper peptide cream to the periphery of the skin ulcers has healed the fissured skin and prevented further ulcer development. It should be emphasized that copper peptides are only to be used for "at-risk" skin in the stage of pre-ulcer dermatitis to help prevent further skin breakdown. It is not approved for the treatment of open skin ulcers.


Avian Respiration

Birds have evolved a respiratory system that enables them to fly. Flying is a high-energy process and requires a lot of oxygen. Furthermore, many birds fly in high altitudes where the concentration of oxygen in low. How did birds evolve a respiratory system that is so unique?

Decades of research by paleontologists have shown that birds evolved from therapods, meat-eating dinosaurs (Figure 20.14). In fact, fossil evidence shows that meat-eating dinosaurs that lived more than 100 million years ago had a similar flow-through respiratory system with lungs and air sacs. Archaeopteryx and Xiaotingia , for example, were flying dinosaurs and are believed to be early precursors of birds.

Figure 20.14.
(a) Birds have a flow-through respiratory system in which air flows unidirectionally from the posterior sacs into the lungs, then into the anterior air sacs. The air sacs connect to openings in hollow bones. (b) Dinosaurs, from which birds descended, have similar hollow bones and are believed to have had a similar respiratory system. (credit b: modification of work by Zina Deretsky, National Science Foundation)

Most of us consider that dinosaurs are extinct. However, modern birds are descendants of avian dinosaurs. The respiratory system of modern birds has been evolving for hundreds of millions of years.

All mammals have lungs that are the main organs for breathing. Lung capacity has evolved to support the animal’s activities. During inhalation, the lungs expand with air, and oxygen diffuses across the lung’s surface and enters the bloodstream. During exhalation, the lungs expel air and lung volume decreases. In the next few sections, the process of human breathing will be explained.


Why does cardiac muscle contraction take more time than striated muscle contraction?

Is it because T-Tubule in cardiac muscle doesn't as well developed as the tubule in striated muscle?

I'm not 100% sure if I am answering the right question. This could be one of two things--if you are asking about why skeletal muscles can contract right away and cardiac muscles can't, it has to do with tetany. If you can contract without any wait time, then you can keep contracting so quickly that the muscle never has time to relax. In skeletal muscle this can be ok if you want to sustain a contraction. On the other hand, in cardiac muscle this would be deadly because the heart needs to relax in oder to fill with blood (diastole). In order to achieve this, the refractory period (how long it takes before the ion pumps can repolarize the membrane) of cardiac muscle is longer. Skeletal and cardiac muscles have different ion pumps which explains the difference in how specific ions behave in the contraction cycle. This means that there is more time before the cardiac muscle can contract compared to a striated muscle contraction.

If on the other hand you are talking about the actual speed of contraction (one cycle) of cardiac versus skeletal muscle the answer gets a bit more complicated. The speed of contraction itself is called twitch, and even among skeletal muscle you have variance (anywhere from 10-100 ms). Cardiac muscle is around 300 ms, meaning the actual muscle contraction takes 300ms (vs 100ms at most for skeletal muscle).

To understand twitch more, you can take a look at fast and slow twitch muscles. Type I slow twitch skeletal muscles are usually bright red, filled with myoglobin, have tons of mitochondria, and work by utilizing O2 to aerobically make energy (ATP) for contraction. These fibers make and split ATP at a slow rate. They take longer to contract and generate less force, but can contract for sustained periods of time. An example is muscle for posture--back muscles.

Type II fast twitch skeletal muscle fibers tend to look pale and have much less myoglobin (less O2) and fewer mitochondria. On the other hand they have lots of glycogen--they get the energy they need to contract by anaerobic means, which takes significantly less time than aerobic metabolism. These fibers make and split ATP at a fast rate. These muscle contract more quickly and with more force, but the contraction cannot be sustained (remember anaerobic=less energy overall than aerobic per cycle). An example is muscles that move your eyes. Many muscle are a mix of fast and slow twitch fibers.

Heart muscle fibers contract even more slowly than Type II slow twitch skeletal muscles. They are completely dependent on O2 as an energy source, and have even more mitochondria than a skeletal slow twitch muscle. At the same time cardiac muscle contraction requires a LOT of ATP. Although I can't seem to find a direct source saying so, I would assume that this means that even though cardiac muscle can make ATP at a faster rate, there is an increased demand, and the ATP may even be split at a slower rate. Since ATP splitting/use is directly proportional to contraction rate, this should be why cardiac muscle contracts slower than skeletal muscle.

*Edit--also, to make things even more complicated, heart rate/and cardiac contraction time is modulated by hormones, calcium levels, etc.


How to Prevent Scabs from Forming

It’s interesting to note that scabs don’t always form on wounds that are healing. In fact, if you dress wounds properly, it is often possible to prevent unsightly scabby crusts forming on the skin.

For example, the Journal of Tissue Viability reported that covering a wound with an air and water-tight dressing prevents scabs from forming. This is because the wound is kept moist and this prevents a scab developing on the healing wound. 13


CONCLUDING REMARKS AND REMAINING QUESTIONS

Previous studies have established the contribution of skin appendages to wound healing. How wounding stimuli recruit stem cells for re-epithelialization is not fully understood. Further understanding of the molecular mechanisms underlying the plasticity of epithelial stem cells in the hair follicle will be necessary to design strategies to efficiently exploit stem cells to enhance tissue regeneration during wound healing. At the same time, it is now clear that wound stimuli can trigger the skin to engage embryonic programs to regenerate hair follicles in adult mice. The relationship between scarless healing and the ability to regenerate epidermal appendages in the wound site is currently unclear. Wound-induced scar formation and epidermal appendage regeneration likely share some common signals or mechanisms. However, it is unknown how the mechanisms that lead to these two distinct consequences of wound healing are synchronized. For example, it is still unclear whether precluding scar formation is a prerequisite to permit the skin to regenerate its appendage or whether the addition of morphogenetic signals in the presence of scar formation can promote epidermal appendage formation. To integrate our understanding of wound healing and appendage regeneration, it will be important to dissect how molecular signals that are activated at each stage of the wound-healing process influence the behavior of each skin cell type and how these signals ultimately promote scarring and/or appendage regeneration.

Interestingly, epidermal appendage regeneration also impacts surrounding cells. This concept is illustrated by a study that showed that epithelial stabilization of β-catenin in adult skin, known to trigger de novo hair follicle formation, confers embryonic characteristics to surrounding dermal cells (Collins et al. 2011). These observations suggest that epidermal appendage formation is not merely a result of regenerative healing, but may be allowing regenerative healing of surrounding dermal cells. Importantly, on amputation of the mouse digit tip, regeneration of underlying mesenchymal bone occurs only in association with nail regeneration (Fig. 4) (Borgens 1982 Zhao and Neufeld 1995 Mohammad et al. 1999 Takeo et al. 2013). Wound healing following digit amputations proximal to the visible nail plate lacks nail regeneration and ends with scarring. These studies highlight the possibility that epidermal appendage formation emits multiple morphogens that signal to other cell types in a paracrine manner. Little is known about the interplay between heterotypic cells that coordinately orchestrate wound healing and regeneration. Dissecting the molecular crosstalk between epidermal appendage regeneration and dermal repair may provide important clues to instruct dermal cells to engage embryonic/regenerative programs and reduce scarring. These future studies hold the promise to develop novel and innovative approaches to exploit our cumulative understanding of signals that govern epidermal appendage regeneration and wound healing.

Relationship between nail regeneration and digit regeneration. Alcian blue/alizarin red staining of mouse digit at 5 weeks after distal (A), or proximal (B) amputation. When a digit is amputated at the distal level, both nail and underlying mesenchymal digit bone regenerates A, while neither nail nor digit bone regenerates from proximal amputation B. (Panel B is from Takeo et al. 2013 reproduced, with permission.)