Constitutive PGC-1α Overexpression in Skeletal Muscle Does Not Improve Morphological Outcome in Mouse Models of Brain Irradiation or Cortical Stroke

Huntington's disease (HD) is caused by CAG repeat expansion in the huntingtin (HTT) gene. Skeletal muscle wasting alongside central pathology is a well-recognized phenomenon seen in patients with HD and HD mouse models. HD muscle atrophy progresses with disease and affects prognosis and quality of life. Satellite cells, progenitors of mature skeletal muscle fibers, are essential for proliferation, differentiation, and repair of muscle tissue in response to muscle injury or exercise. In this study, we aim to investigate the effect of mutant HTT on the differentiation and regeneration capacity of HD muscle by employing in vitro mononuclear skeletal muscle cell isolation and in vivo acute muscle damage model in R6/2 mice. We found that, similar to R6/2 adult mice, neonatal R6/2 mice also exhibit a significant reduction in myofiber width and morphological changes in gastrocnemius and soleus muscles compared to WT mice. Cardiotoxin (CTX)-induced acute muscle damage in R6/2 and WT mice showed that the Pax7+ satellite cell pool was dampened in R6/2 mice at 4 weeks post-injection, and R6/2 mice exhibited an altered inflammatory profile in response to acute damage. Our results suggest that, in addition to the mutant HTT degenerative effects in mature muscle fibers, expression of mutant HTT in satellite cells might alter developmental and regenerative processes to contribute to the progressive muscle mass loss in HD. Taken together, the results presented here encourage further studies evaluating the underlying mechanisms of satellite cell dysfunction in HD mouse models.

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Genomic Profiling Reveals That Transient Adipogenic Activation Is a Hallmark of Mouse Models of Skeletal Muscle Regeneration

PLoS ONE ◽

10.1371/journal.pone.0071084 ◽

2013 ◽

Vol 8 (8) ◽

pp. e71084 ◽

Cited By ~ 33

Author(s):

Laura Lukjanenko ◽

Sophie Brachat ◽

Eliane Pierrel ◽

Estelle Lach-Trifilieff ◽

Jerome N. Feige

Keyword(s):

Skeletal Muscle ◽

Mouse Models ◽

Muscle Regeneration ◽

Skeletal Muscle Regeneration ◽

Genomic Profiling

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Immune Responses to Human Induced Pluripotent Stem Cells and their Derived Myogenic Progenitors Are Mediated by Different Mechanisms in Humanized Mice

10.1101/550699 ◽

2019 ◽

Author(s):

Basma Benabdallah ◽

Cynthia Désaulniers-Langevin ◽

Marie-Lyn Goyer ◽

Chloé Colas ◽

Chantale Maltais ◽

...

Keyword(s):

Skeletal Muscle ◽

Stem Cells ◽

Immune Responses ◽

Nk Cells ◽

Mouse Models ◽

Adoptive Transfer ◽

Pluripotent Stem Cells ◽

Humanized Mouse ◽

Humanized Mouse Models ◽

Induced Pluripotent

ABSTRACTIt is still unclear if immune responses will compromise the large scale utilization of cell therapies derived from human induced pluripotent stem cells (hiPSCs). To answer this question, we used humanized mouse models and evaluated the engraftment in skeletal muscle of myoblasts derived either directly from a muscle biopsy or differentiated from hiPSCs or fibroblasts. Our results showed that while allogeneic grafts were rejected, engraftment of autologous cells was tolerated, indicating reprogramming and differentiation procedures are not immunogenic. We also demonstrated that hiPSC-derived myogenic progenitors, in opposition to hiPSCs, are not targeted by natural killer (NK) cells both in vitro and in vivo. Yet, adoptive transfer of NK cells can prevent the formation of hiPSC-derived teratoma. Overall, our findings suggest that hiPSC-derived muscular therapies will be tolerated in presence of a competent human immune system and highlight the risk of forming a teratoma if using partially differentiated autologous human cells.HighlightshiPSC-derived myofibers are tolerated in autologous humanized mouse modelsInfiltration of autologous T cells is not predictive of successful skeletal muscle engraftmentAdoptive transfer of NK cells prevents the formation of hiPSCs derived teratomasNK cells are unable to reject established teratomas

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L-tyrosine supplementation is not therapeutic for skeletal muscle dysfunction in zebrafish and mouse models of dominant skeletal muscle α-actin nemaline myopathy

10.1101/218016 ◽

2017 ◽

Cited By ~ 1

Author(s):

Adriana M. Messineo ◽

Charlotte Gineste ◽

Tamar E. Sztal ◽

Elyshia L. McNamara ◽

Christophe Vilmen ◽

...

Keyword(s):

Skeletal Muscle ◽

Animal Models ◽

Mouse Models ◽

Muscle Function ◽

Skeletal Muscles ◽

Nemaline Myopathy ◽

Quadriceps Muscle ◽

Therapeutic Benefit ◽

Skeletal Muscle Function ◽

Tyrosine Concentration

ABSTRACTNemaline myopathy (NM) is a skeletal muscle disorder with no curative treatment. Although L-tyrosine administration has been indicated to provide benefit to patients, previous studies have been limited due to sample size or not testing for raised L-tyrosine levels. We evaluated the efficacy of L-tyrosine treatment to improve skeletal muscle function in three animal models of NM caused by skeletal muscle α-actin (ACTA1) mutations. Firstly we determined the maximum safest L-tyrosine concentration for inclusion in the water of wildtype zebrafish. We then treated NM TgACTA1D286G-eGFP zebrafish from 24 hours post fertilization with the highest safe L-tyrosine dose (10 µM). At 6 days post fertilization, no significant improvement was detected in skeletal muscle function (swimming distance). We also determined the highest safe L-tyrosine dose for dietary L-tyrosine supplementation to wildtype mice. Next we treated the NM TgACTA1D286G mouse model continuously from preconception with 2% L-tyrosine supplemented to regular feed. We examined skeletal muscles at 6–7 weeks using indicators of skeletal muscle integrity: bodyweight, voluntary running wheel and rotarod performance, all parameters previously shown to be reduced in TgACTA1D286G mice. The L-tyrosine treatment regime did not result in any improvement of these parameters, despite significant elevation of free L-tyrosine levels in sera (57%) and quadriceps muscle (45%) of treated TgACTA1D286G mice. Additionally, we assessed the effects of 4 weeks of 2% L-tyrosine dietary supplementation on skeletal muscle function of older (6-7 month old) NM TgACTA1D286G and KIActa1H40Y mice. This dosing regime did not improve decreased bodyweight, nor the mechanical properties, energy metabolism, or atrophy of skeletal muscles in these NM models. Together these findings demonstrate that with the treatment regimes and doses evaluated, L-tyrosine does not therapeutically modulate dysfunctional skeletal muscles in NM animal models with dominant ACTA1 mutations. Therefore this study yields important information on aspects of the clinical utility of L-tyrosine for ACTA1 NM.Summary statementDespite previous encouraging reports, this study utilising zebrafish and mouse models of nemaline myopathy shows no therapeutic benefit on skeletal muscle functionality in response to L-tyrosine supplementation.

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Autophagy, apoptosis, and mitochondria: molecular integration and physiological relevance in skeletal muscle

AJP Cell Physiology ◽

10.1152/ajpcell.00261.2018 ◽

2019 ◽

Vol 317 (1) ◽

pp. C111-C130 ◽

Cited By ~ 9

Author(s):

Darin Bloemberg ◽

Joe Quadrilatero

Keyword(s):

Skeletal Muscle ◽

Human Physiology ◽

Mouse Models ◽

Cellular Level ◽

Cellular Systems ◽

Biological Mechanisms ◽

Pharmacological Manipulation ◽

Physiological Relevance ◽

Individual Importance ◽

Death Signals

Apoptosis and autophagy are processes resulting from the integration of cellular stress and death signals. Their individual importance is highlighted by the lethality of various mouse models missing apoptosis or autophagy-related genes. In addition to their independent roles, significant overlap exists with respect to the signals that stimulate these processes as well as their effector consequences. While these cellular systems exemplify the programming redundancies that underlie many fundamental biological mechanisms, their intertwined relationship means that dysfunction can promote pathology. Although both autophagic and apoptotic signaling are active in skeletal muscle during various diseases and atrophy, their specific roles here are somewhat unique. Given our growing understanding of how specific changes at the cellular level impact whole-organism physiology, there is an equally growing interest in pharmacological manipulation of apoptosis and/or autophagy for altering human physiology and health.

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Disease Affects Bdnf Expression in Synaptic and Extrasynaptic Regions of Skeletal Muscle of Three SBMA Mouse Models

International Journal of Molecular Sciences ◽

10.3390/ijms20061314 ◽

2019 ◽

Vol 20 (6) ◽

pp. 1314 ◽

Cited By ~ 4

Author(s):

Katherine Halievski ◽

Samir Nath ◽

Masahisa Katsuno ◽

Hiroaki Adachi ◽

Gen Sobue ◽

...

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Mouse Models ◽

Contractile Function ◽

Muscular Atrophy ◽

Synaptic Function ◽

Bdnf Expression ◽

Gene Dysregulation ◽

Synaptic Region ◽

Spinal Bulbar Muscular Atrophy

Spinal bulbar muscular atrophy (SBMA) is a slowly progressive, androgen-dependent neuromuscular disease in men that is characterized by both muscle and synaptic dysfunction. Because gene expression in muscle is heterogeneous, with synaptic myonuclei expressing genes that regulate synaptic function and extrasynaptic myonuclei expressing genes to regulate contractile function, we used quantitative PCR to compare gene expression in these two domains of muscle from three different mouse models of SBMA: the “97Q” model that ubiquitously expresses mutant human androgen receptor (AR), the 113Q knock-in (KI) model that expresses humanized mouse AR with an expanded glutamine tract, and the “myogenic” model that overexpresses wild-type rat AR only in skeletal muscle. We were particularly interested in neurotrophic factors because of their role in maintaining neuromuscular function via effects on both muscle and synaptic function, and their implicated role in SBMA. We confirmed previous reports of the enriched expression of select genes (e.g., the acetylcholine receptor) in the synaptic region of muscle, and are the first to report the synaptic enrichment of others (e.g., glial cell line-derived neurotrophic factor). Interestingly, all three models displayed comparably dysregulated expression of most genes examined in both the synaptic and extrasynaptic domains of muscle, with only modest differences between regions and models. These findings of comprehensive gene dysregulation in muscle support the emerging view that skeletal muscle may be a prime therapeutic target for restoring function of both muscles and motoneurons in SBMA.

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Characterization of skeletal muscle in mouse models of osteogenesis imperfecta and myostatin deficiency

10.32469/10355/8435 ◽

2010 ◽

Author(s):

Bettina A. Weber

Keyword(s):

Skeletal Muscle ◽

Osteogenesis Imperfecta ◽

Mouse Models

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Myostatin Inhibition Using ActRIIB-mFc Does Not Produce Weight Gain or Strength in the Nebulin Conditional KO Mouse

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nly120 ◽

2018 ◽

Vol 78 (2) ◽

pp. 130-139 ◽

Cited By ~ 3

Author(s):

Jennifer A Tinklenberg ◽

Emily M Siebers ◽

Margaret J Beatka ◽

Brittany A Fickau ◽

Samuel Ayres ◽

...

Keyword(s):

Skeletal Muscle ◽

Weight Gain ◽

Mouse Model ◽

Mouse Models ◽

Clinical Symptoms ◽

Conditional Knockout ◽

Variable Degree ◽

Pathological Changes ◽

Myostatin Inhibition ◽

Nemaline Bodies

Abstract Mutations in at least 12 genes are responsible for a group of congenital skeletal muscle diseases known as nemaline myopathies (NMs). NMs are associated with a range of clinical symptoms and pathological changes often including the presence of cytoplasmic rod-like structures (nemaline bodies) and myofiber hypotrophy. Our recent work has identified a variable degree of behavioral benefit when treating 2 NM mouse models due to mutations in Acta1 with myostatin inhibition. This study is focused on the effects of delivering ActRIIB-mFc (Acceleron; a myostatin inhibitor) to the nebulin conditional knockout KO (Neb cKO) mouse model of NM. Treatment of Neb cKO mice with ActRIIB-mFc did not produce increases in weight gain, strength, myofiber size, or hypertrophic pathway signaling. Overall, our studies demonstrate a lack of response in Neb cKO mice to myostatin inhibition, which differs from the response observed when treating other NM models.

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