Disuse and aging: same problem, different outcomes

Many of the changes that accompany physical inactivity coincide with those that occur during aging. These changes are generally grouped under the term of 'disuse' (or "lack of use" or "inappropriately modulated stimulation"). Studies of long-term space travel have revealed that weightlessness in space also induces changes resembling those of aging and physical inactivity. The relationship between disuse (due to bed rest, insufficient exercise, or lack of gravity) and aging has some definite practical implications. As life expectancy is lenghtened in all populations worldwide, the number of elderly with varying degrees of disability leading to reduced physical activity also increases. Changes induced by bed rest as a consequence of disease may also be superimposed on aging changes and further diminish physiologic reserves and accelerate pathology. Therefore, the study of disuse, irrespective of its etiology, may serve as a model for understanding not only some of the functional changes induced by lack of activity and/or gravity but also some of the disabilities of old age. Indeed, a better understanding of disuse phenomena will make it possible to establish programs of prevention and rehabilitation that will ameliorate both disuse and aging deficits.     

The involvement of the ubiquitin proteasome system in human skeletal muscle remodelling and atrophy

Skeletal muscle exhibits great plasticity in response to altered activity levels, ultimately resulting in tissue remodelling and substantial changes in mass. Animal research would suggest that the ubiquitin proteasome system, in particular the ubiquitin ligases MAFbx/atrogin-1 and MuRF1, are instrumental to the processes underlying these changes. This review article therefore examines the role of proteasomal-mediated protein degradation in human skeletal muscle in health and disease. Specifically, the effects of exercise, disuse and inflammatory disease states on the ubiquitin proteasome system in human skeletal muscle are examined. The article also identifies several inconsistencies between published human studies and data obtained from animal models of muscle atrophy, highlighting the need for a more comprehensive examination of the molecular events responsible for modulating muscle mass in humans.     

Tissue transglutaminase in normal and abnormal wound healing: Review article

Summary. A complex series of events involving inflammation, cell migration and proliferation, ECM stabilisation and remodelling, neovascularisation and apoptosis are crucial to the tissue response to injury. Wound healing involves the dynamic interactions of multiple cells types with components of the extracellular matrix (ECM) and growth factors. Impaired wound healing as a consequence of aging, injury or disease may lead to serious disabilities and poor quality of life. Abnormal wound healing may also lead to inflammatory and fibrotic conditions (such as renal and pulmonary fibrosis). Therefore identification of the molecular events underlying wound repair is essential to develop new effective treatments in support to patients and the wound care sector.Recent advances in the understating of the physiological functions of tissue transglutaminase a multi functional protein cross-linking enzyme which stabilises tissues have demonstrated that its biological activities interrelate with wound healing phases at multiple levels. This review describes our view of the function of tissue transglutaminase in wound repair under normal and pathological situations and highlights its potential as a strategic therapeutic target in the development of new treatments to improve wound healing and prevent scarring.     

The Order of Exercise during Concurrent Training for Rehabilitation Does Not Alter Acute Genetic Expression,Mitochondrial Enzyme Activity or Improvements in Muscle Function

Concurrent exercise combines different modes of exercise (e.g., aerobic and resistance) into one training protocol, providing stimuli meant to increase muscle strength, aerobic capacity and mass. As disuse is associated with decrements in strength, aerobic capacity and muscle size concurrent training is an attractive modality for rehabilitation. However, interference between the signaling pathways may result in preferential improvements for one of the exercise modes. We recruited 18 young adults (10 ♂, 8 ♀) to determine if order of exercise mode during concurrent training would differentially affect gene expression, protein content and measures of strength and aerobic capacity after 2 weeks of knee-brace induced disuse. Concurrent exercise sessions were performed 3x/week for 6 weeks at gradually increasing intensities either with endurance exercise preceding (END>RES) or following (RES>END) resistance exercise. Biopsies were collected from the vastus lateralis before, 3 h after the first exercise bout and 48 h after the end of training. Concurrent exercise altered the expression of genes involved in mitochondrial biogenesis (PGC-1α, PRC, PPARγ), hypertrophy (PGC-1α4, REDD2, Rheb) and atrophy (MuRF-1, Runx1), increased electron transport chain complex protein content, citrate synthase and mitochondrial cytochrome c oxidase enzyme activity, muscle mass, maximum isometric strength and VO_2peak. However, the order in which exercise was completed (END>RES or RES>END) only affected the protein content of mitochondrial complex II subunit. In conclusion, concurrent exercise training is an effective modality for the rehabilitation of the loss of skeletal muscle mass, maximum strength, and peak aerobic capacity resulting from disuse, regardless of the order in which the modes of exercise are performed.     

Gene expression profile of adhesion and extracellular matrix molecules during early stages of skeletal muscle regeneration

Skeletal muscle regeneration implies the coordination of myogenesis with the recruitment of myeloid cells and extracellular matrix (ECM) remodelling. Currently, there are no specific biomarkers to diagnose the severity and prognosis of muscle lesions. In order to investigate the gene expression profile of extracellular matrix and adhesion molecules, as premises of homo‐ or heterocellular cooperation and milestones for skeletal muscle regeneration, we performed a gene expression analysis for genes involved in cellular cooperation, migration and ECM remodelling in a mouse model of acute crush injury. The results obtained at two early time‐points post‐injury were compared to a GSE5413 data set from two other trauma models. Third day post‐injury, when inflammatory cells invaded, genes associated with cell‐matrix interactions and migration were up‐regulated. After day 5, as myoblast migration and differentiation started, genes for basement membrane constituents were found down‐regulated, whereas genes for ECM molecules, macrophage, myoblast adhesion, and migration receptors were up‐regulated. However, the profile and the induction time varied according to the experimental model, with only few genes being constantly up‐regulated. Gene up‐regulation was higher, delayed and more diverse following more severe trauma. Moreover, one of the most up‐regulated genes was periostin, suggestive for severe muscle damage and unfavourable architecture restoration.     

Arthritis; the use of physical therapy as an aspect of management

In some cases arthritis can be controlled even in the acute stage by physical therapy alone. In many cases, recovery depends on how thoroughly and intelligently such methods are applied.Heat, ultrasound and therapeutic baths relieve pain and spasm, permitting greater freedom in passive and active exercise. Exercise is necessary in maintaining and restoring function to arthritic limbs. Because the atrophy produced by rheumatoid arthritis is greater than that due to mere disuse for the same length of time, resistive exercise is especially valuable in building muscle, and this can be carried out even during active inflammation. Without exercise the muscles weaken and throw a greater burden on the already disabled joints. At the same time the patient must be relieved of undue stress and trauma by planned rest, splinting, bed posture and, later, crutches and other aids to ambulation. Efforts should be made to prevent contractures and deformities. Occupational therapy increases muscle strength, range of motion, work tolerance and mental status. A dynamic and carefully planned rehabilitation program hastens restoration of the patient's independence and usefulness.     

ARTHRITIS—The Use of Physical Therapy as an Aspect of Management

In some cases arthritis can be controlled even in the acute stage by physical therapy alone. In many cases, recovery depends on how thoroughly and intelligently such methods are applied.Heat, ultrasound and therapeutic baths relieve pain and spasm, permitting greater freedom in passive and active exercise. Exercise is necessary in maintaining and restoring function to arthritic limbs. Because the atrophy produced by rheumatoid arthritis is greater than that due to mere disuse for the same length of time, resistive exercise is especially valuable in building muscle, and this can be carried out even during active inflammation. Without exercise the muscles weaken and throw a greater burden on the already disabled joints.At the same time the patient must be relieved of undue stress and trauma by planned rest, splinting, bed posture and, later, crutches and other aids to ambulation. Efforts should be made to prevent contractures and deformities.Occupational therapy increases muscle strength, range of motion, work tolerance and mental status. A dynamic and carefully planned rehabilitation program hastens restoration of the patient''s independence and usefulness.     

Tissue remodelling in liver diseases

Tissue remodelling is a dynamic process that occurs during fetal or adult life and involves a modification of the original organization and function of a tissue. Tissue remodelling is observed in physiological and pathological conditions such as during wound healing or in the mammary gland during the course of pregnancy. In this review we will discuss the remodelling occurring in the liver as a consequence of chronic inflammation, as observed in chronic hepatitis, or as a consequence of hepatocellular carcinoma (HCC) progression in more detail. We will consider how altered deposition and turn-over of extracellular matrix (ECM) proteins could lead to development of liver fibrosis, and how the exacerbation of fibrosis could underlie the development of cirrhosis. The involvement of inflammatory and anti-inflammatory cytokines commonly used as therapeutic agents, such as Interferon-a, is then evaluated with a particular focus on modulation of ECM proteolysis. Finally, we analyze the role of alterations of the surrounding microenvironment including ECM, growth factors, cytokines and membrane receptors for ECM ligands in the development of HCC and in its invasive behaviour.     

Nitric oxide and voluntary exercise together promote quadriceps hypertrophy and increase vascular density in female 18-mo-old mice

Age-related sarcopenia reduces the size, strength, and function of muscle, and the diameter of muscle fibers. It also disrupts the dystrophin-glycoprotein complex, dislocating nitric oxide synthase 1 (NOS-1) and reducing sarcolemmal integrity. This study of quadriceps muscle in 18-mo-old mice showed that NO-donor treatment with isosorbide dinitrate (I) for 6 wk, in combination with voluntary exercise for 3 wk, increased muscle mass by 25% and stimulated cell proliferation. The resulting fiber hypertrophy was accompanied by a lower ratio of protein:DNA, consistent with myogenic-cell hyperplasia. Treatment enhanced the ratio of NOS-1:β-dystroglycan in correlation with fiber diameter, improved sarcolemmal integrity, and increased vascular density after an increase in vascular endothelial growth factor protein at 3 wk. Results demonstrate that age-related muscle refractoriness to exercise can be overcome with NO-donor treatment. Since activation of muscle stem cells and vascular perfusion are limiting factors in the maintenance, regeneration, and growth of aged muscle, results suggest the feasibility of using NO-donor drugs to combat atrophy and muscle ischemia. Improved function and quality of life from the NO-amplified effects of exercise may be useful in aging and other conditions such as disuse, insulin resistance, or microgravity.     

The interaction between urokinase receptor and vitronectin in cell adhesion and signalling

The extracellular matrix (ECM) is a complex structural entity surrounding and supporting cells present in all tissue and organs. Cell-matrix interactions play fundamental roles during embryonic development, morphogenesis, tissue homoeostasis, wound healing, and tumourigenesis. Cell-matrix communication is kept in balance by physical contact and by transmembrane integrin receptors providing the dynamic link between the extracellular and intracellular environments through bi-directional signalling. The urokinase-type plasminogen activator receptor (uPAR) is a plasma membrane receptor overexpressed during inflammation and in almost all human cancers. One of its functions is to endorse ECM remodelling through the activation of plasminogen and downstream proteases, including matrix-metalloproteases (MMPs). Beside its role in ECM degradation, uPAR modulates cell-matrix contact through a direct engagement with the ECM component, vitronectin (Vn), and by regulating the activity state of integrins thus promoting or inhibiting integrin signalling and integrin-mediated cell adhesion to other ECM components, like fibronectin and collagen. In this review we have centred our attention on the non-proteolytic function of uPAR as a mediator of cell adhesion and downstream signalling.     

TGFβ, smooth muscle cells and coronary artery disease: a review

Excessive vascular smooth muscle cell (SMC) proliferation, migration and extracellular matrix (ECM) synthesis are key events in the development of intimal hyperplasia, a pathophysiological response to acute or chronic sources of vascular damage that can lead to occlusive narrowing of the vessel lumen. Atherosclerosis, the primary cause of coronary artery disease, is characterised by chronic vascular inflammation and dyslipidemia, while revascularisation surgeries such as coronary stenting and bypass grafting represent acute forms of vascular injury. Gene knockouts of transforming growth factor-beta (TGFβ), its receptors and downstream signalling proteins have demonstrated the importance of this pleiotropic cytokine during vasculogenesis and in the maintenance of vascular homeostasis. Dysregulated TGFβ signalling is a hallmark of many vascular diseases, and has been associated with the induction of pathological vascular cell phenotypes, fibrosis and ECM remodelling. Here we present an overview of TGFβ signalling in SMCs, highlighting the ways in which this multifaceted cytokine regulates SMC behaviour and phenotype in cardiovascular diseases driven by intimal hyperplasia.     

Training-induced changes in muscle CSA, muscle strength, EMG, and rate of force development in elderly subjects after long-term unilateral disuse.

The ability to develop muscle force rapidly may be a very important factor to prevent a fall and to perform other tasks of daily life. However, information is still lacking on the range of training-induced neuromuscular adaptations in elderly humans recovering from a period of disuse. Therefore, the present study examined the effect of three types of training regimes after unilateral prolonged disuse and subsequent hip-replacement surgery on maximal muscle strength, rapid muscle force [rate of force development (RFD)], muscle activation, and muscle size. Thirty-six subjects (60-86 yr) were randomized to a 12-wk rehabilitation program consisting of either 1) strength training (3 times/wk for 12 wk), 2) electrical muscle stimulation (1 h/day for 12 wk), or 3) standard rehabilitation (1 h/day for 12 wk). The nonoperated side did not receive any intervention and thereby served as a within-subject control. Thirty subjects completed the trial. In the strength-training group, significant increases were observed in maximal isometric muscle strength (24%, P < 0.01), contractile RFD (26-45%, P < 0.05), and contractile impulse (27-32%, P < 0.05). No significant changes were seen in the two other training groups or in the nontrained legs of all three groups. Mean electromyogram signal amplitude of vastus lateralis was larger in the strength-training than in the standard-rehabilitation group at 5 and 12 wk (P < 0.05). In contrast to traditional physiotherapy and electrical stimulation, strength training increased muscle mass, maximal isometric strength, RFD, and muscle activation in elderly men and women recovering from long-term muscle disuse and subsequent hip surgery. The improvement in both muscle mass and neural function is likely to have important functional implications for elderly individuals.     

Improving physical activity in COPD: towards a new paradigm

Chronic obstructive pulmonary disease (COPD) is a debilitating disease affecting patients in daily life, both physically and emotionally. Symptoms such as dyspnea and muscle fatigue, lead to exercise intolerance, which, together with behavioral issues, trigger physical inactivity, a key feature of COPD. Physical inactivity is associated with adverse clinical outcomes, including hospitalization and all-cause mortality. Increasing activity levels is crucial for effective management strategies and could lead to improved long-term outcomes. In this review we summarize objective and subjective instruments for evaluating physical activity and focus on interventions such as pulmonary rehabilitation or bronchodilators aimed at increasing activity levels. To date, only limited evidence exists to support the effectiveness of these interventions. We suggest that a multimodal approach comprising pulmonary rehabilitation, pharmacotherapy, and counselling programs aimed at addressing emotional and behavioural aspects of COPD may be an effective way to increase physical activity and improve health status in the long term.     

Matrix metalloproteinases in liver injury,repair and fibrosis

The liver is a large highly vascularized organ with a central function in metabolic homeostasis, detoxification, and immunity. Due to its roles, the liver is frequently exposed to various insults which can cause cell death and hepatic dysfunction. Alternatively, the liver has a remarkable ability to self-repair and regenerate after injury. Liver injury and regeneration have both been linked to complex extracellular matrix (ECM) related pathways. While normal degradation of ECM components is an important feature of tissue repair and remodeling, irregular ECM turnover contributes to a variety of liver diseases. Matrix metalloproteinases (MMPs) are the main enzymes implicated in ECM degradation. MMPs not only remodel the ECM, but also regulate immune responses. In this review, we highlight some of the MMP-attributed roles in acute and chronic liver injury and emphasize the need for further experimentation to better understand their functions during hepatic physiological conditions and disease progression.     

Physical exercise attenuates age-associated reduction in endothelium-reparative capacity of endothelial progenitor cells by increasing CXCR4/JAK-2 signaling in healthy men

Endothelial progenitor cells (EPCs) play an important role in repairing endothelial injury. Aging is associated with EPC dysfunction. Physical exercise has a beneficial impact on EPC activity. However, whether physical exercise can enhance the endothelial repair capacity of EPCs in healthy men with aging is not clear. Here, we investigated the effects of physical exercise on reendothelialization capacity and CXC chemokine receptor four (CXCR4) signaling in human EPCs. Before and after 12-week exercise, EPCs were isolated from elderly and young men. In vitro function and in vivo reendothelialization capacity of EPCs in a mouse model of carotid artery injury were measured. The expression of CXCR4 and its downstream signaling target Janus kinase-2 (JAK-2) were determined. Before exercise, in vitro function and in vivo reendothelialization capacity of EPCs were significantly reduced in elderly men compared with young men. After exercise intervention, in vitro function and in vivo reendothelialization capacity of EPCs from elderly men were markedly enhanced. Physical exercise increased a higher CXCR4 protein expression and higher JAK-2 phosphorylation levels of EPCs. The augmentation in reendothelialization capacity of EPCs was closely correlated with the upregulation of CXCR4/JAK-2 signaling and improvement of endothelial function. This study demonstrates for the first time that physical exercise attenuates age-associated reduction in endothelium-reparative capacity of EPCs by increasing CXCR4/JAK-2 signaling. Our findings provide insight into the novel mechanisms of physical exercise as a lifestyle intervention strategy to promote vascular health in aging population.