Effect of voluntary wheel-running exercise on muscles of the mdx mouse

Carter, Gregory T.; Wineinger, Mark A.; Walsh, Sandra A.; Horasek, S. J.; Abresch, Richard T.; Fowler, William M.

doi:10.1016/0960-8966(94)00063-f

Cited by 86 publications

(82 citation statements)

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“…A single episode of excessive physical exercise is known to cause acute damage to the skeletal muscle (33) and is thought to induce focal lesions in muscle fibers, leading to cell necrosis (34)(35)(36). Dystrophin deficiency in mdx mice leads to impaired performance in running (37)(38)(39) and more pronounced muscle damage than in control mice during sudden exercise (39,40), suggesting a structural role for this protein. Type VI collagen deficiency results in myopathy in both the human (30) and the mouse (31), although Col6a1 Ϫ/Ϫ mice did not show any significant reduction in activity during a 2-month voluntary running period in wheel cages (31).…”

Section: Discussionmentioning

confidence: 99%

Lack of type XV collagen causes a skeletal myopathy and cardiovascular defects in mice

Eklund

Piuhola

Komulainen

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

168

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Type XV collagen occurs widely in the basement membrane zones of tissues, but its function is unknown. To understand the biological role of this protein, a null mutation in the Col15a1 gene was introduced into the germ line of mice. Despite the complete lack of type XV collagen, the mutant mice developed and reproduced normally, and they were indistinguishable from their wild-type littermates. However, Col15a1-deficient mice showed progressive histological changes characteristic for muscular diseases after 3 months of age, and they were more vulnerable than controls to exercise-induced muscle injury. Despite the antiangiogenic role of type XV collagen-derived endostatin, the development of the vasculature appeared normal in the null mice. Nevertheless, ultrastructural analyses revealed collapsed capillaries and endothelial cell degeneration in the heart and skeletal muscle. Furthermore, perfused hearts showed a diminished inotropic response, and exercise resulted in cardiac injury, changes that mimic early or mild heart disease. Thus, type XV collagen appears to function as a structural component needed to stabilize skeletal muscle cells and microvessels.T ype XV collagen belongs to the heterogeneous group of non-fibril-forming collagens and is thought to be a homotrimer consisting of three ␣1(XV) collagen chains (1). It is characterized by a central highly interrupted triple helical domain and large N-and C-terminal noncollagenous domains (2-4), and it has been shown to be a chondroitin sulfate proteoglycan (5). Type XV collagen mRNAs are expressed in many tissues, but the highest mRNA levels in the mouse can be detected in the heart and skeletal muscle (4). The protein is shown by immunostaining to have a widespread tissue distribution and has been localized mainly to the basement membrane zones, although it can also be found in the fibrillar collagen matrix of some tissues (6, 7). Its function is not known, however.In terms of primary structure, type XV collagen is highly homologous with type XVIII collagen, and together they form a distinct subgroup among the collagens (1, 3). They have thrombospondin-1 sequence homology in the N terminus, seven homologous collagenous domains, and highly homologous Cterminal noncollagenous domains. Type XVIII collagen is the precursor of endostatin, which has been shown to have a potent antiangiogenic effect (8), and the highest degree of homology between collagen types XV and XVIII involves the C-terminal endostatin sequence. The corresponding fragment in type XV collagen has also been shown to have antiangiogenic activity (9, 10).To understand the biological function and significance of type XV collagen, we generated a mouse strain lacking in ␣1(XV) collagen chains by site-specific Cre-loxP-mediated deletion in embryonic stem (ES) cells (11). The data suggest a structural role for type XV collagen in providing mechanical stability between cells and the extracellular matrix in skeletal muscle fibers and microvessels. Col15a1 deficiency leads to functional rather than struct...

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Section: Discussionmentioning

confidence: 99%

Lack of type XV collagen causes a skeletal myopathy and cardiovascular defects in mice

Eklund

Piuhola

Komulainen

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

168

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“…Progressive muscle cell loss and weakness is a major contributing factor to reduced exercise capacity. Mild exercise intolerance is recapitulated by the mdx mouse model of DMD (Carter et al 1995). DMD, BMD, α-, β-, and γ-sarcoglycanopathies as well as other neuromuscular diseases are characterized by reduced nNOSμ expression, particularly sarcolemmal nNOSμ, due to disruption of the dystrophin glycoprotein complex.…”

Section: Nnosμ Function In Neuromuscular Diseasementioning

confidence: 99%

nNOS regulation of skeletal muscle fatigue and exercise performance

Percival

2011

Biophys Rev

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Neuronal nitric oxide synthases (nNOS) are Ca 2+ /calmodulin-activated enzymes that synthesize the gaseous messenger nitric oxide (NO). nNOSμ and the recently described nNOSβ, both spliced nNOS isoforms, are important enzymatic sources of NO in skeletal muscle, a tissue long considered to be a paradigmatic system for studying NO-dependent redox signaling. nNOS is indispensable for skeletal muscle integrity and contractile performance, and deregulation of nNOSμ signaling is a common pathogenic feature of many neuromuscular diseases. Recent evidence suggests that both nNOSμ and nNOSβ regulate skeletal muscle size, strength, and fatigue resistance, making them important players in exercise performance. nNOSμ acts as an activity sensor and appears to assist skeletal muscle adaptation to new functional demands, particularly those of endurance exercise. Prolonged inactivity leads to nNOS-mediated muscle atrophy through a FoxO-dependent pathway. nNOS also plays a role in modulating exercise performance in neuromuscular disease. In the mdx mouse model of Duchenne muscular dystrophy, defective nNOS signaling is thought to restrict contractile capacity of working muscle in two ways: loss of sarcolemmal nNOSμ causes excessive ischemic damage while residual cytosolic nNOSμ contributes to hypernitrosylation of the ryanodine receptor, causing pathogenic Ca 2+ leak. This defect in Ca 2+ handling promotes muscle damage, weakness, and fatigue. This review addresses these recent advances in the understanding of nNOS-dependent redox regulation of skeletal muscle function and exercise performance under physiological and neuromuscular disease conditions.

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“…In the past, many patients with muscular dystrophy were advised not to exercise because of the belief that too much exercise might lead to overuse weakness {Johnson, 1971; Johnson, 1971;Carter, 1995;Fowler, 1984;Petrof, 1998}. Yet, in their Cochrane review on muscle strength training and aerobic exercise training for patients with muscle diseases, Voet concluded that moderate-intensity strength training in MD and FSHD appeared not to be harmful, although there was insufficient evidence to establish its benefit {Voet et al , 2010}.…”

Section: Physical Exercisementioning

confidence: 99%