Loss of dystrophin expression in skeletal muscle is associated with senescence of macrophages and endothelial cells.

2021 ◽  
Author(s):  
Laura V. Young ◽  
William Morrison ◽  
Craig Campbell ◽  
Emma C. Moore ◽  
Michel G. Arsenault ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Endothelial Cells ◽  
Cellular Senescence ◽  
Neuromuscular Disorder ◽  
Muscle Pathology ◽  
Mdx Mice ◽  
Matrix Remodeling ◽  
Dystrophic Muscle ◽  
Dividing Cells ◽  
And Function

Cellular senescence is the irreversible arrest of normally dividing cells and is driven by cell cycle inhibitory proteins such as p16, p21 and p53. When cells enter senescence, they secrete a host of proinflammatory factors known as the senescence associated secretory phenotype which has deleterious effects on surrounding cells and tissues. Little is known of the role of senescence in Duchenne Muscular Dystrophy (DMD), the fatal X-linked neuromuscular disorder typified by chronic inflammation, extracellular matrix remodeling and a progressive loss in muscle mass and function. Here, we demonstrate using C57-mdx (8-week-old) and D2-mdx mice (4-week and 8-week-old), two mouse models of DMD, that cells displaying canonical markers of senescence are found within skeletal muscle. 8-week-old D2-mdx mice, which display severe muscle pathology, had greater numbers of senescent cells associated with areas of inflammation which were mostly Cdkn1a-positive macrophages while in C57-mdx muscle, senescent populations were endothelial cells and macrophages localized to newly regenerated myofibers. Interestingly, this pattern was similar to cardiotoxin (CTX)-injured wildtype (WT) muscle which experienced a transient senescent response. Dystrophic muscle demonstrated significant upregulations in senescence pathway genes (Cdkn1a (p21), Cdkn2a (p16INK4A), Trp53 (p53)) which correlated with the quantity of SA-b-Gal-positive cells. These results highlight an underexplored role for cellular senescence in murine dystrophic muscle.

scholarly journals Resveratrol Promotes Hypertrophy in Wildtype Skeletal Muscle and Reduces Muscle Necrosis and Gene Expression of Inflammatory Markers in Mdx Mice

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 853
Author(s):  
Keryn G. Woodman ◽  
Chantal A. Coles ◽  
Shireen R. Lamandé ◽  
Jason D. White
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Immune Cell ◽  
Neuromuscular Disorder ◽  
Voluntary Exercise ◽  
Mdx Mice ◽  
Dystrophic Muscle ◽  
Cell Markers ◽  
Muscle Necrosis ◽  
Exercise Induced

Duchenne muscular dystrophy (DMD) is a progressive fatal neuromuscular disorder with no cure. Therapies to restore dystrophin deficiency have been approved in some jurisdictions but long-term effectiveness is yet to be established. There is a need to develop alternative strategies to treat DMD. Resveratrol is a nutraceutical with anti-inflammatory properties. Previous studies have shown high doses (100–400 mg/kg bodyweight/day) benefit mdx mice. We treated 4-week-old mdx and wildtype mice with a lower dose of resveratrol (5 mg/kg bodyweight/day) for 15 weeks. Voluntary exercise was used to test if a lower dosage than previously tested could reduce exercise-induced damage where a greater inflammatory infiltrate is present. We found resveratrol promoted skeletal muscle hypertrophy in wildtype mice. In dystrophic muscle, resveratrol reduced exercise-induced muscle necrosis. Gene expression of immune cell markers, CD86 and CD163 were reduced; however, signalling targets associated with resveratrol’s mechanism of action including Sirt1 and NF-κB were unchanged. In conclusion, a lower dose of resveratrol compared to the dosage used by other studies reduced necrosis and gene expression of inflammatory cell markers in dystrophic muscle suggesting it as a therapeutic candidate for treating DMD.

scholarly journals Treatment with rGDF11 does not improve the dystrophic muscle pathology of mdx mice

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Fabrizio Rinaldi ◽  
Yu Zhang ◽  
Ricardo Mondragon-Gonzalez ◽  
Jeffrey Harvey ◽  
Rita C. R. Perlingeiro
Keyword(s):  
Muscle Pathology ◽  
Mdx Mice ◽  
Dystrophic Muscle

scholarly journals Early metabolic changes measured by 1H MRS in healthy and dystrophic muscle after injury

2012 ◽  
Vol 113 (5) ◽  
pp. 808-816 ◽  
Author(s):  
Su Xu ◽  
Stephen J. P. Pratt ◽  
Espen E. Spangenburg ◽  
Richard M. Lovering
Keyword(s):  
Skeletal Muscle ◽  
Muscle Injury ◽  
Tibialis Anterior Muscle ◽  
Metabolic Changes ◽  
Mdx Mice ◽  
Resonance Spectroscopy ◽  
Dystrophic Muscle ◽  
1H Mrs ◽  
Skeletal Muscle Injury

Skeletal muscle injury is often assessed by clinical findings (history, pain, tenderness, strength loss), by imaging, or by invasive techniques. The purpose of this work was to determine if in vivo proton magnetic resonance spectroscopy (1H MRS) could reveal metabolic changes in murine skeletal muscle after contraction-induced injury. We compared findings in the tibialis anterior muscle from both healthy wild-type (WT) muscles (C57BL/10 mice) and dystrophic ( mdx mice) muscles (an animal model for human Duchenne muscular dystrophy) before and after contraction-induced injury. A mild in vivo eccentric injury protocol was used due to the high susceptibility of mdx muscles to injury. As expected, mdx mice sustained a greater loss of force (81%) after injury compared with WT (42%). In the uninjured muscles, choline (Cho) levels were 47% lower in the mdx muscles compared with WT muscles. In mdx mice, taurine levels decreased 17%, and Cho levels increased 25% in injured muscles compared with uninjured mdx muscles. Intramyocellular lipids and total muscle lipid levels increased significantly after injury but only in WT. The increase in lipid was confirmed using a permeable lipophilic fluorescence dye. In summary, loss of torque after injury was associated with alterations in muscle metabolite levels that may contribute to the overall injury response in mdx mice. These results show that it is possible to obtain meaningful in vivo 1H MRS regarding skeletal muscle injury.

scholarly journals Role of Age-Related Mitochondrial Dysfunction in Sarcopenia

2020 ◽  
Vol 21 (15) ◽  
pp. 5236 ◽  
Author(s):  
Evelyn Ferri ◽  
Emanuele Marzetti ◽  
Riccardo Calvani ◽  
Anna Picca ◽  
Matteo Cesari ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cellular Senescence ◽  
Significant Loss ◽  
Muscle Aging ◽  
Age Related ◽  
Mitochondrial Functions ◽  
Health Quality ◽  
Skeletal Muscle Aging ◽  
And Function

Skeletal muscle aging is associated with a significant loss of skeletal muscle strength and power (i.e., dynapenia), muscle mass and quality of life, a phenomenon known as sarcopenia. This condition affects nearly one-third of the older population and is one of the main factors leading to negative health outcomes in geriatric patients. Notwithstanding the exact mechanisms responsible for sarcopenia are not fully understood, mitochondria have emerged as one of the central regulators of sarcopenia. In fact, there is a wide consensus on the assumption that the loss of mitochondrial integrity in myocytes is the main factor leading to muscle degeneration. Mitochondria are also key players in senescence. It has been largely proven that the modulation of mitochondrial functions can induce the death of senescent cells and that removal of senescent cells improves musculoskeletal health, quality, and function. In this review, the crosstalk among mitochondria, cellular senescence, and sarcopenia will be discussed with the aim to elucidate the role that the musculoskeletal cellular senescence may play in the onset of sarcopenia through the mediation of mitochondria.

scholarly journals Human thrombocytopenia is associated with structural abnormalities of the endothelium that are ameliorated by glucocorticosteroid administration

Blood ◽  
1986 ◽  
Vol 67 (1) ◽  
pp. 203-206 ◽  
Author(s):  
CS Kitchens ◽  
JF Pendergast
Keyword(s):  
Skeletal Muscle ◽  
Endothelial Cells ◽  
Normal Structure ◽  
Structure And Function ◽  
Capillary Endothelium ◽  
Severe Thrombocytopenia ◽  
Structural Abnormalities ◽  
And Function

Abstract Capillary fragility is characteristic of severe thrombocytopenia. This mechanical weakness may not be solely accounted for by decreased ability of platelets to repair endothelial breaks. Platelets may have a role in maintaining endothelial hemostasis. This laboratory has demonstrated thinning of capillary endothelium in experimental thrombocytopenia. We now report similar findings in human thrombocytopenia. Capillary endothelium supplying either skin or skeletal muscle was found to have a mean thickness only half that of normal as well as frequent very thinned areas, including some fenestrations. All findings reverted toward normal after four days of prednisone administration at a time the degree of thrombocytopenia was equally severe. These findings are consistent with the hypothesis that platelets are necessary for normal structure and function of endothelial cells and that glucocorticosteroid administration may ameliorate the pathophysiology of thrombocytopenia.

scholarly journals Overexpression of Galgt2 in skeletal muscle prevents injury resulting from eccentric contractions in both mdx and wild-type mice

2009 ◽  
Vol 296 (3) ◽  
pp. C476-C488 ◽  
Author(s):  
Paul T. Martin ◽  
Rui Xu ◽  
Louise R. Rodino-Klapac ◽  
Elaine Oglesbay ◽  
Marybeth Camboni ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Transgenic Mice ◽  
Skeletal Muscles ◽  
Eccentric Contractions ◽  
Cytotoxic T Cell ◽  
Muscle Pathology ◽  
Mdx Mice ◽  
Specific Force ◽  
Wild Type

The cytotoxic T cell (CT) GalNAc transferase, or Galgt2, is a UDP-GalNAc:β1,4- N-acetylgalactosaminyltransferase that is localized to the neuromuscular synapse in adult skeletal muscle, where it creates the synaptic CT carbohydrate antigen {GalNAcβ1,4[NeuAc(orGc)α2, 3]Galβ1,4GlcNAcβ-}. Overexpression of Galgt2 in the skeletal muscles of transgenic mice inhibits the development of muscular dystrophy in mdx mice, a model for Duchenne muscular dystrophy. Here, we provide physiological evidence as to how Galgt2 may inhibit the development of muscle pathology in mdx animals. Both Galgt2 transgenic wild-type and mdx skeletal muscles showed a marked improvement in normalized isometric force during repetitive eccentric contractions relative to nontransgenic littermates, even using a paradigm where nontransgenic muscles had force reductions of 95% or more. Muscles from Galgt2 transgenic mice, however, showed a significant decrement in normalized specific force and in hindlimb and forelimb grip strength at some ages. Overexpression of Galgt2 in muscles of young adult mdx mice, where Galgt2 has no effect on muscle size, also caused a significant decrease in force drop during eccentric contractions and increased normalized specific force. A comparison of Galgt2 and microdystrophin overexpression using a therapeutically relevant intravascular gene delivery protocol showed Galgt2 was as effective as microdystrophin at preventing loss of force during eccentric contractions. These experiments provide a mechanism to explain why Galgt2 overexpression inhibits muscular dystrophy in mdx muscles. That overexpression also prevents loss of force in nondystrophic muscles suggests that Galgt2 is a therapeutic target with broad potential applications.

Muscle-specific overexpression of IGF-I improves E-C coupling in skeletal muscle fibers from dystrophic mdx mice

2008 ◽  
Vol 294 (1) ◽  
pp. C161-C168 ◽  
Author(s):  
Jonathan D. Schertzer ◽  
Chris van der Poel ◽  
Thea Shavlakadze ◽  
Miranda D. Grounds ◽  
Gordon S. Lynch
Keyword(s):  
Skeletal Muscle ◽  
Growth Factor ◽  
Muscle Fibers ◽  
Transcript Level ◽  
Direct Result ◽  
Mdx Mice ◽  
Contractile Apparatus ◽  
Dystrophic Muscle ◽  
Insulin Growth Factor ◽  
Igf I

Duchenne muscular dystrophy (DMD) is a lethal X-linked disease caused by the absence of functional dystrophin. Abnormal excitation-contraction (E-C) coupling has been reported in dystrophic muscle fibers from mdx mice, and alterations in E-C coupling components may occur as a direct result of dystrophin deficiency. We hypothesized that muscle-specific overexpression of insulin-growth factor-1 (IGF-I) would reduce E-C coupling failure in mdx muscle. Mechanically skinned extensor digitorum longus muscle fibers from mdx mice displayed a faster decline in depolarization-induced force responses (DIFR); however, there were no differences in sarcoplasmic reticulum (SR)-mediated Ca2+ resequestration or in the properties of the contractile apparatus when compared with nondystrophic controls. The rate of DIFR decline was restored to control levels in fibers from transgenic mdx mice that overexpressed IGF-I in skeletal muscle ( mdx/IGF-I mice). Dystrophic muscles have a lower transcript level of a specific dihydropyridine receptor (DHPR) isoform, and IGF-I-mediated changes in E-C coupling were associated with increased transcript levels of specific DHPR isoforms involved in Ca2+ regulation. Importantly, IGF-I overexpression also increased the sensitivity of the contractile apparatus to Ca2+. The results demonstrate that IGF-I can ameliorate fundamental aspects of E-C coupling failure in dystrophic muscle fibers and that these effects are important for the improvements in cellular function induced by this growth factor.

scholarly journals Extensive but Coordinated Reorganization of the Membrane Skeleton in Myofibers of Dystrophic (mdx) Mice

1999 ◽  
Vol 144 (6) ◽  
pp. 1259-1270 ◽  
Author(s):  
McRae W. Williams ◽  
Robert J. Bloch
Keyword(s):  
Skeletal Muscle ◽  
Membrane Proteins ◽  
Muscle Fibers ◽  
Membrane Skeleton ◽  
Confocal Imaging ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Intracellular Membrane ◽  
Dystrophic Muscle ◽  
Dihydropyridine Receptors

We used immunofluorescence techniques and confocal imaging to study the organization of the membrane skeleton of skeletal muscle fibers of mdx mice, which lack dystrophin. β-Spectrin is normally found at the sarcolemma in costameres, a rectilinear array of longitudinal strands and elements overlying Z and M lines. However, in the skeletal muscle of mdx mice, β-spectrin tends to be absent from the sarcolemma over M lines and the longitudinal strands may be disrupted or missing. Other proteins of the membrane and associated cytoskeleton, including syntrophin, β-dystroglycan, vinculin, and Na,K-ATPase are also concentrated in costameres, in control myofibers, and mdx muscle. They also distribute into the same altered sarcolemmal arrays that contain β-spectrin. Utrophin, which is expressed in mdx muscle, also codistributes with β-spectrin at the mutant sarcolemma. By contrast, the distribution of structural and intracellular membrane proteins, including α-actinin, the Ca-ATPase and dihydropyridine receptors, is not affected, even at sites close to the sarcolemma. Our results suggest that in myofibers of the mdx mouse, the membrane- associated cytoskeleton, but not the nearby myoplasm, undergoes widespread coordinated changes in organization. These changes may contribute to the fragility of the sarcolemma of dystrophic muscle.

scholarly journals Systemic Microdystrophin Gene Delivery Improves Skeletal Muscle Structure and Function in Old Dystrophic mdx Mice

2008 ◽  
Vol 16 (4) ◽  
pp. 657-664 ◽  
Author(s):  
Paul Gregorevic ◽  
Michael J Blankinship ◽  
James M Allen ◽  
Jeffrey S Chamberlain
Keyword(s):  
Skeletal Muscle ◽  
Gene Delivery ◽  
Structure And Function ◽  
Mdx Mice ◽  
Muscle Structure ◽  
And Function

scholarly journals Molecular Basis for the Therapeutic Effects of Exercise on Mitochondrial Defects

2021 ◽  
Vol 11 ◽  
Author(s):  
Jonathan M. Memme ◽  
David A. Hood
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Dysfunction ◽  
Muscle Pathology ◽  
Therapeutic Effects ◽  
Atp Production ◽  
Muscle Aging ◽  
Mitochondrial Defects ◽  
Aging Muscle ◽  
Skeletal Muscle Aging ◽  
And Function

Mitochondrial dysfunction is common to many organ system disorders, including skeletal muscle. Aging muscle and diseases of muscle are often accompanied by defective mitochondrial ATP production. This manuscript will focus on the pre-clinical evidence supporting the use of regular exercise to improve defective mitochondrial metabolism and function in skeletal muscle, through the stimulation of mitochondrial turnover. Examples from aging muscle, muscle-specific mutations and cancer cachexia will be discussed. We will also examine the effects of exercise on the important mitochondrial regulators PGC-1α, and Parkin, and summarize the effects of exercise to reverse mitochondrial dysfunction (e.g., ROS production, apoptotic susceptibility, cardiolipin synthesis) in muscle pathology. This paper will illustrate the breadth and benefits of exercise to serve as “mitochondrial medicine” with age and disease.

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