Browsing by Author "Rebolledo, Daniela L."

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    Denervation Drives YAP/TAZ Activation in Muscular Fibro/Adipogenic Progenitors
    (2023) Gallardo, Felipe S.; Cordova-Casanova, Adriana; Bock-Pereda, Alexia; Rebolledo, Daniela L.; Ravasio, Andrea; Casar, Juan Carlos; Brandan, Enrique
    Loss of motoneuron innervation (denervation) is a hallmark of neurodegeneration and aging of the skeletal muscle. Denervation induces fibrosis, a response attributed to the activation and expansion of resident fibro/adipogenic progenitors (FAPs), i.e., multipotent stromal cells with myofibroblast potential. Using in vivo and in silico approaches, we revealed FAPs as a novel cell population that activates the transcriptional coregulators YAP/TAZ in response to skeletal muscle denervation. Here, we found that denervation induces the expression and transcriptional activity of YAP/TAZ in whole muscle lysates. Using the Pdgfra(H2B:EGFP/+) transgenic reporter mice to trace FAPs, we demonstrated that denervation leads to increased YAP expression that accumulates within FAPs nuclei. Consistently, re-analysis of published single-nucleus RNA sequencing (snRNA-seq) data indicates that FAPs from denervated muscles have a higher YAP/TAZ signature level than control FAPs. Thus, our work provides the foundations to address the functional role of YAP/TAZ in FAPs in a neurogenic pathological context, which could be applied to develop novel therapeutic approaches for the treatment of muscle disorders triggered by motoneuron degeneration.
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    Denervation-induced skeletal muscle fibrosis is mediated by CTGF/CCN2 independently of TGF-β
    (2019) Rebolledo, Daniela L.; González, David; Faundez Contreras, Jennifer; Contreras Saavedra, Osvaldo Isaías; Vio Lagos, Carlos P.; Murphy Ullrich, Joanne E.; Lipson, Kenneth E.; Brandan, Enrique; Rebolledo, Daniela L.; González, David; Faundez Contreras, Jennifer; Contreras Saavedra, Osvaldo Isaías; Vio Lagos, Carlos P.; Murphy Ullrich, Joanne E.; Lipson, Kenneth E.; Brandan, Enrique
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    Episodic Binge-like Ethanol Reduces Skeletal Muscle Strength Associated with Atrophy, Fibrosis, and Inflammation in Young Rats
    (2023) Cáceres-Ayala, Constanza; Mira, Rodrigo G.; Acuña, María José; Brandan, Enrique; Cerpa Nebott, Waldo; Rebolledo, Daniela L.
    Binge Drinking (BD) corresponds to episodes of ingestion of large amounts of ethanol in a short time, typically ≤2 h. BD occurs across all populations, but young and sports-related people are especially vulnerable. However, the short- and long-term effects of episodic BD on skeletal muscle function have been poorly explored. Young rats were randomized into two groups: control and episodic Binge-Like ethanol protocol (BEP) (ethanol 3 g/kg IP, 4 episodes of 2-days ON-2-days OFF paradigm). Muscle function was evaluated two weeks after the last BEP episode. We found that rats exposed to BEP presented decreased muscle strength and increased fatigability, compared with control animals. Furthermore, we observed that skeletal muscle from rats exposed to BEP presented muscle atrophy, evidenced by reduced fiber size and increased expression of atrophic genes. We also observed that BEP induced fibrotic and inflammation markers, accompanied by mislocalization of nNOSµ and high levels of protein nitration. Our findings suggest that episodic binge-like ethanol exposure alters contractile capacity and increases fatigue by mechanisms involving atrophy, fibrosis, and inflammation, which remain for at least two weeks after ethanol clearance. These pathological features are common to several neuromuscular diseases and might affect muscle performance and health in the long term.
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    Intracellular amyloid formation in muscle cells of Aβ-transgenic Caenorhabditis elegans: determinants and physiological role in copper detoxification
    (2009) Minniti, Alicia N.; Rebolledo, Daniela L.; Grez, Paula M.; Fadic, Ricardo; Aldunate, Rebeca; Volitakis, Irene; Cherny, Robert A.; Opazo, Carlos; Masters, Colin; Bush, Ashley I.; Inestrosa, Nibaldo C.
    Background: The amyloid beta-peptide is a ubiquitous peptide, which is prone to aggregate forming soluble toxic oligomers and insoluble less-toxic aggregates. The intrinsic and external/environmental factors that determine A beta aggregation in vivo are poorly understood, as well as the cellular meaning of this process itself. Genetic data as well as cell biological and biochemical evidence strongly support the hypothesis that A beta is a major player in the onset and development of Alzheimer's disease. In addition, it is also known that A beta is involved in Inclusion Body Myositis, a common myopathy of the elderly in which the peptide accumulates intracellularly.
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    Sarcolemmal targeting of nNOS mu improves contractile function of mdx muscle
    (OXFORD UNIV PRESS, 2016) Rebolledo, Daniela L.; Kim, Min Jeong; Whitehead, Nicholas P.; Adams, Marvin E.; Froehner, Stanley C.
    Nitric oxide (NO) is a key regulator of skeletal muscle function and metabolism, including vasoregulation, mitochondrial function, glucose uptake, fatigue and excitation-contraction coupling. The main generator of NO in skeletal muscle is the muscle-specific form of neuronal nitric oxide synthase (nNOS mu) produced by the NOS1 gene. Skeletal muscle nNOS mu is predominantly localized at the sarcolemma by interaction with the dystrophin protein complex (DPC). In Duchenne muscular dystrophy (DMD), loss of dystrophin leads to the mislocalization of nNOS mu from the sarcolemma to the cytosol. This perturbation has been shown to impair contractile function and cause muscle fatigue in dystrophic (mdx) mice. Here, we investigated the effect of restoring sarcolemmal nNOS mu on muscle contractile function in mdx mice. To achieve this, we designed a modified form of nNOS mu (NOS-M) that is targeted to the sarcolemma by palmitoylation, even in the absence of the DPC. When expressed specifically in mdx skeletal muscle, NOS-M significantly attenuates force loss owing to damaging eccentric contractions and repetitive isometric contractions (fatigue), while also improving force recovery after fatigue. Expression of unmodified nNOS mu at similar levels does not lead to sarcolemmal association and fails to improve muscle function. Aside from the benefits of sarcolemmal-localized NO production, NOS-M also increased the surface membrane levels of utrophin and other DPC proteins, including beta-dystroglycan, alpha-syntrophin and alpha-dystrobrevin in mdx muscle. These results suggest that the expression of NOS-M in skeletal muscle may be therapeutically beneficial in DMD and other muscle diseases characterized by the loss of nNOS mu from the sarcolemma.
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    The functional and molecular effects of problematic alcohol consumption on skeletal muscle: a focus on athletic performance
    (2022) Caceres-Ayala, Constanza; Pautassi, Ricardo M.; Acuña, María José; Cerpa Nebott, Waldo; Rebolledo, Daniela L.
    Background: Chronic alcohol misuse is associated with alcoholic myopathy, characterized by skeletal muscle weakness and atrophy. Moreover, there is evidence that sports-related people seem to exhibit a greater prevalence of problematic alcohol consumption, especially binge drinking (BD), which might not cause alcoholic myopathy but can negatively impact muscle function and amateur and professional athletic performance. Objective: To review the literature concerning the effects of alcohol consumption on skeletal muscle function and structure that can affect muscle performance. Methodology: We examined the currently available literature (PubMed, Google Scholars) to develop a narrative review summarizing the knowledge about the effects of alcohol on skeletal muscle function and exercise performance, obtained from studies in human beings and animal models for problematic alcohol consumption. Results: Exercise- and sport-based studies indicate that alcohol consumption can negatively affect muscle recovery after vigorous exercise, especially in men, while women seem less affected. Clinical studies and pre-clinical laboratory research have led to the knowledge of some of the mechanisms involved in alcohol-related muscle dysfunction, including an imbalance between anabolic and catabolic pathways, reduced regeneration, increased inflammation and fibrosis, and deficiencies in energetic balance and mitochondrial function. These pathological features can appear not only under chronic alcohol misuse but also in other alcohol consumption patterns. Conclusions: Most laboratory-based studies use chronic or acute alcohol exposure, while episodic BD, the most common drinking pattern in amateur and professional athletes, is underrepresented. Nevertheless, alcohol consumption negatively affects skeletal muscle health through different mechanisms, which collectively might contribute to reduced sports performance.
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    The inhibition of CTGF/CCN2 activity improves muscle and locomotor function in a murine ALS model
    (2018) González, David; Rebolledo, Daniela L.; Correa, Lina M.; Court G., Felipe; Cerpa Nebott, Waldo Francisco; Lipson, Kenneth E.; Van Zundert, Brigitte; Brandan, Enrique