Airway smooth muscle (ASM) is the major effector of excessive airway narrowing in asthma. Changes in some of the mechanical properties of ASM could contribute to excessive narrowing and have not been systematically studied in human ASM from nonasthmatic and asthmatic subjects.Human ASM strips (eight asthmatic and six nonasthmatic) were studied at in situ length and force was normalised to maximal force induced by electric field stimulation (EFS). Measurements included: passive and active force versus length before and after length adaptation, the forcevelocity relationship, maximal shortening and force recovery after length oscillation. Force was converted to stress by dividing by cross-sectional area of muscle.The only functional differences were that the asthmatic tissue was stiffer at longer lengths (p,0.05) and oscillatory strain reduced isometric force in response to EFS by 19% as opposed to 36% in nonasthmatics (p,0.01).The mechanical properties of human ASM from asthmatic and nonasthmatic subjects are comparable except for increased passive stiffness and attenuated decline in force generation after an oscillatory perturbation. These data may relate to reduced bronchodilation induced by a deep inspiration in asthmatic subjects.KEYWORDS: Airway hyperresponsiveness, airway mechanics, asthma, force-velocity relationships, length-tension relationships, smooth muscle A sthma is characterised by exaggerated airway narrowing caused by airway smooth muscle (ASM) shortening. However, it is unclear whether there is a fundamental phenotypic change in the ASM itself or if the nonmuscle components of the airway wall or surrounding lung parenchyma are primary contributors to this airway hyperresponsiveness (AHR) [1,2]. A major hurdle to a clear understanding of ASM contractile function in disease has been the limited data. Of the 12 studies in which ASM mechanical properties have been compared in asthmatic and nonasthmatic tissue, seven have demonstrated no differences [3][4][5][6][7][8][9], while five have shown increases in force, shortening or agonist sensitivity [10][11][12][13][14].We have previously demonstrated that ASM cell bundles carefully dissected from the tracheas of nonasthmatic subjects whose lungs were donated for medical research provide a valuable, high quality tissue preparation for study of the mechanical properties of ASM [15].We showed that the mechanical properties of nonasthmatic ASM were similar to those measured in other mammalian models. This is in contrast to previous studies which suggested that human ASM produced less force per unit area and shortened less than the ASM of other mammals [16].The purpose of this study was to re-evaluate a series of hypotheses related to ASM mechanics that have been suggested as possible defects in asthmatic ASM function and potential contributors to AHR. These include determining whether asthmatic ASM produces more stress (force per unit cross-sectional area of muscle) than nonasthmatic ASM [17,18]; whether the length-tension relationship of asthmat...

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Progressive limb and girdle muscle atrophy leading to loss of ambulation is a hallmark of dysferlinopathies, which include limb-girdle muscular dystrophy type 2B and Miyoshi myopathy. However, animal models fail to fully reproduce the disease severity observed in humans, with dysferlin-null (Dysf) mice exhibiting minor muscle damage and weakness without dramatic ambulatory dysfunction. As we have previously reported significant Dysf expression in blood vessels, we investigated the role of vascular function in development of muscle pathology by generating a Dysf-deficient mouse model with vascular disease. This was achieved by crossing Dysf mice with ApoE mice, which have high levels of nonHDL-associated cholesterol. Double-knockout DysfApoE mice exhibited severe ambulatory dysfunction by 11 months of age. In limb-girdle muscles, histology confirmed dramatic muscle wasting, fibrofatty replacement, and myofiber damage in DysfApoE mice without affecting the ratio of centrally nucleated myofibers. Although there were no major changes in ex vivo diaphragm and soleus muscle function, histological analyses revealed these muscles to be untouched by damage and remodelling. In all, these data suggest that cholesterol may be deleterious to dysferlinopathic muscle and lead to ambulatory dysfunction. Moreover, differences in plasma lipid handling between mice and humans could be a key factor affecting dysferlinopathy severity.