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17 pages, 2896 KiB

Open AccessArticle

Ranolazine Counteracts Strength Impairment and Oxidative Stress in Aged Sarcopenic Mice

by Alessio Torcinaro, Donato Cappetta, Francesca De Santa, Marialucia Telesca, Massimiliano Leigheb, Liberato Berrino, Konrad Urbanek, Antonella De Angelis and Elisabetta Ferraro

Metabolites 2022, 12(7), 663; https://doi.org/10.3390/metabo12070663 - 18 Jul 2022

Cited by 5 | Viewed by 2634

Abstract

Sarcopenia is defined as the loss of muscle mass associated with reduced strength leading to poor quality of life in elderly people. The decline of skeletal muscle performance is characterized by bioenergetic impairment and severe oxidative stress, and does not always strictly correlate [...] Read more.

Sarcopenia is defined as the loss of muscle mass associated with reduced strength leading to poor quality of life in elderly people. The decline of skeletal muscle performance is characterized by bioenergetic impairment and severe oxidative stress, and does not always strictly correlate with muscle mass loss. We chose to investigate the ability of the metabolic modulator Ranolazine to counteract skeletal muscle dysfunctions that occur with aging. For this purpose, we treated aged C57BL/6 mice with Ranolazine/vehicle for 14 days and collected the tibialis anterior and gastrocnemius muscles for histological and gene expression analyses, respectively. We found that Ranolazine treatment significantly increased the muscle strength of aged mice. At the histological level, we found an increase in centrally nucleated fibers associated with an up-regulation of genes encoding MyoD, Periostin and Osteopontin, thus suggesting a remodeling of the muscle even in the absence of physical exercise. Notably, these beneficial effects of Ranolazine were also accompanied by an up-regulation of antioxidant and mitochondrial genes as well as of NADH-dehydrogenase activity, together with a more efficient protection from oxidative damage in the skeletal muscle. These data indicate that the protection of muscle from oxidative stress by Ranolazine might represent a valuable approach to increase skeletal muscle strength in elderly populations. Full article

(This article belongs to the Special Issue Skeletal Muscle Atrophy and Metabolic Adaptation)

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11 pages, 1305 KiB

Open AccessCommunication

Reticulon-1C Involvement in Muscle Regeneration

by Federica Rossin, Elena Avitabile, Giorgia Catarinella, Ersilia Fornetti, Stefano Testa, Serafina Oliverio, Cesare Gargioli, Stefano Cannata, Lucia Latella and Federica Di Sano

Metabolites 2021, 11(12), 855; https://doi.org/10.3390/metabo11120855 - 8 Dec 2021

Viewed by 2395

Abstract

Skeletal muscle is a very dynamic and plastic tissue, being essential for posture, locomotion and respiratory movement. Muscle atrophy or genetic muscle disorders, such as muscular dystrophies, are characterized by myofiber degeneration and replacement with fibrotic tissue. Recent studies suggest that changes in [...] Read more.

Skeletal muscle is a very dynamic and plastic tissue, being essential for posture, locomotion and respiratory movement. Muscle atrophy or genetic muscle disorders, such as muscular dystrophies, are characterized by myofiber degeneration and replacement with fibrotic tissue. Recent studies suggest that changes in muscle metabolism such as mitochondrial dysfunction and dysregulation of intracellular Ca²⁺ homeostasis are implicated in many adverse conditions affecting skeletal muscle. Accumulating evidence also suggests that ER stress may play an important part in the pathogenesis of inflammatory myopathies and genetic muscle disorders. Among the different known proteins regulating ER structure and function, we focused on RTN-1C, a member of the reticulon proteins family localized on the ER membrane. We previously demonstrated that RTN-1C expression modulates cytosolic calcium concentration and ER stress pathway. Moreover, we recently reported a role for the reticulon protein in autophagy regulation. In this study, we found that muscle differentiation process positively correlates with RTN-1C expression and UPR pathway up-regulation during myogenesis. To better characterize the role of the reticulon protein alongside myogenic and muscle regenerative processes, we performed in vivo experiments using either a model of muscle injury or a photogenic model for Duchenne muscular dystrophy. The obtained results revealed RTN-1C up-regulation in mice undergoing active regeneration and localization in the injured myofibers. The presented results strongly suggested that RTN-1C, as a protein involved in key aspects of muscle metabolism, may represent a new target to promote muscle regeneration and repair upon injury. Full article

(This article belongs to the Special Issue Skeletal Muscle Atrophy and Metabolic Adaptation)

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13 pages, 4368 KiB

Open AccessArticle

Preliminary Observations on Skeletal Muscle Adaptation and Plasticity in Homer 2^-/- Mice

by Paola Lorenzon, Sandra Furlan, Barbara Ravara, Alessandra Bosutti, Gabriele Massaria, Annalisa Bernareggi, Marina Sciancalepore, Gabor Trautmann, Katharina Block, Dieter Blottner, Paul F. Worley, Sandra Zampieri, Michele Salanova and Pompeo Volpe

Metabolites 2021, 11(9), 642; https://doi.org/10.3390/metabo11090642 - 19 Sep 2021

Cited by 4 | Viewed by 3055

Abstract

Homer represents a diversified family of scaffold and transduction proteins made up of several isoforms. Here, we present preliminary observations on skeletal muscle adaptation and plasticity in a transgenic model of Homer 2^-/- mouse using a multifaceted approach entailing morphometry, quantitative RT-PCR [...] Read more.

Homer represents a diversified family of scaffold and transduction proteins made up of several isoforms. Here, we present preliminary observations on skeletal muscle adaptation and plasticity in a transgenic model of Homer 2^-/- mouse using a multifaceted approach entailing morphometry, quantitative RT-PCR (Reverse Transcription PCR), confocal immunofluorescence, and electrophysiology. Morphometry shows that Soleus muscle (SOL), at variance with Extensor digitorum longus muscle (EDL) and Flexor digitorum brevis muscle (FDB), displays sizable reduction of fibre cross-sectional area compared to the WT counterparts. In SOL of Homer 2^-/- mice, quantitative RT-PCR indicated the upregulation of Atrogin-1 and Muscle ring finger protein 1 (MuRF1) genes, and confocal immunofluorescence showed the decrease of neuromuscular junction (NMJ) Homer content. Electrophysiological measurements of isolated FDB fibres from Homer 2^-/- mice detected the exclusive presence of the adult ε-nAChR isoform excluding denervation. As for NMJ morphology, data were not conclusive, and further work is needed to ascertain whether the null Homer 2 phenotype induces any endplate remodelling. Within the context of adaptation and plasticity, the present data show that Homer 2 is a co-regulator of the normotrophic status in a muscle specific fashion. Full article

(This article belongs to the Special Issue Skeletal Muscle Atrophy and Metabolic Adaptation)

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12 pages, 1364 KiB

Open AccessCommunication

The Leucine Catabolite and Dietary Supplement β-Hydroxy-β-Methyl Butyrate (HMB) as an Epigenetic Regulator in Muscle Progenitor Cells

by Virve Cavallucci and Giovambattista Pani

Metabolites 2021, 11(8), 512; https://doi.org/10.3390/metabo11080512 - 4 Aug 2021

Cited by 7 | Viewed by 4528

Abstract

β-Hydroxy-β-Methyl Butyrate (HMB) is a natural catabolite of leucine deemed to play a role in amino acid signaling and the maintenance of lean muscle mass. Accordingly, HMB is used as a dietary supplement by sportsmen and has shown some clinical effectiveness in preventing [...] Read more.

β-Hydroxy-β-Methyl Butyrate (HMB) is a natural catabolite of leucine deemed to play a role in amino acid signaling and the maintenance of lean muscle mass. Accordingly, HMB is used as a dietary supplement by sportsmen and has shown some clinical effectiveness in preventing muscle wasting in cancer and chronic lung disease, as well as in age-dependent sarcopenia. However, the molecular cascades underlying these beneficial effects are largely unknown. HMB bears a significant structural similarity with Butyrate and β-Hydroxybutyrate (βHB), two compounds recognized for important epigenetic and histone-marking activities in multiple cell types including muscle cells. We asked whether similar chromatin-modifying actions could be assigned to HMB as well. Exposure of murine C2C12 myoblasts to millimolar concentrations of HMB led to an increase in global histone acetylation, as monitored by anti-acetylated lysine immunoblotting, while preventing myotube differentiation. In these effects, HMB resembled, although with less potency, the histone deacetylase (HDAC) inhibitor Sodium Butyrate. However, initial studies did not confirm a direct inhibitory effect of HMB on HDACs in vitro. β-Hydroxybutyrate, a ketone body produced by the liver during starvation or intense exercise, has a modest effect on histone acetylation of C2C12 cells or in vitro HDAC inhibitor activities, and, unlike Butyrate and HMB, did not interfere with myotube formation in a myoblast differentiation assay. Instead, βHB dramatically increased lysine β-hydroxybutyrylation (Kbhb) of histone tails, an epigenetic mark associated with fasting responses and muscle catabolic states. However, when C2C12 cells were exposed to βHB in the presence of equimolar HMB this chromatin modification was drastically reduced, pointing to a role for HMB in attenuating ketosis-associated muscle wasting. In conclusion, while their mechanistic underpinnings remain to be clarified, these preliminary observations highlight novel and potentially important activities of HMB as an epigenetic regulator and βHB antagonist in muscle precursor cells, to be further explored in their biomedical implications. Full article

(This article belongs to the Special Issue Skeletal Muscle Atrophy and Metabolic Adaptation)

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16 pages, 2807 KiB

Open AccessEditor’s ChoiceArticle

Lifelong Aerobic Exercise Alleviates Sarcopenia by Activating Autophagy and Inhibiting Protein Degradation via the AMPK/PGC-1α Signaling Pathway

by Jiling Liang, Hu Zhang, Zhengzhong Zeng, Liangwen Wu, Ying Zhang, Yanju Guo, Jun Lv, Cenyi Wang, Jingjing Fan and Ning Chen

Metabolites 2021, 11(5), 323; https://doi.org/10.3390/metabo11050323 - 18 May 2021

Cited by 47 | Viewed by 6231

Abstract

Sarcopenia is an aging-induced syndrome characterized by a progressive reduction of skeletal muscle mass and strength. Increasing evidence has attested that appropriate and scientific exercise could induce autophagy or optimize the functional status of autophagy, which plays a critical role in senescent muscular [...] Read more.

Sarcopenia is an aging-induced syndrome characterized by a progressive reduction of skeletal muscle mass and strength. Increasing evidence has attested that appropriate and scientific exercise could induce autophagy or optimize the functional status of autophagy, which plays a critical role in senescent muscular dystrophy. As a publicly recognized strategy for extending lifespan and improving the health of the elderly, the underlying mechanisms of lifelong regular aerobic exercise for the prevention of sarcopenia have not been fully elucidated. To explore the role of lifelong aerobic exercise in the beneficial regulation of autophagic signaling pathways in senescent skeletal muscle, the natural aging mice were used as the sarcopenia model and subjected to lifelong treadmill running to evaluate corresponding parameters related to skeletal muscle atrophy and autophagic signaling pathways. Compared with the young control mice, the aged mice showed a significant reduction in skeletal muscle mass, gastrocnemius muscle weight/body weight (GMW/BW) ratio, and cross-sectional areas (CSA) of skeletal muscle fibers (p < 0.01). In contrast, lifelong aerobic exercise effectively rescued these reduced biomarkers associated with muscle atrophy. Moreover, as shown in the activated AMPK/PGC-1α signaling pathway, lifelong aerobic exercise successfully prevented the aging-induced impairment of the ubiquitin-proteasome system (UPS), excessive apoptosis, defective autophagy, and mitochondrial dysfunction. The exercise-induced autophagy suppressed the key regulatory components of the UPS, inhibited excessive apoptosis, and optimized mitochondrial quality control, thereby preventing and delaying aging-induced skeletal muscle atrophy. Full article

(This article belongs to the Special Issue Skeletal Muscle Atrophy and Metabolic Adaptation)

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11 pages, 846 KiB

Open AccessReview

Thyroid Hormone Action in Muscle Atrophy

by Maria Angela De Stefano, Raffaele Ambrosio, Tommaso Porcelli, Gianfranco Orlandino, Domenico Salvatore and Cristina Luongo

Metabolites 2021, 11(11), 730; https://doi.org/10.3390/metabo11110730 - 25 Oct 2021

Cited by 17 | Viewed by 4457

Abstract

Skeletal muscle atrophy is a condition associated with various physiological and pathophysiological conditions, such as denervation, cachexia, and fasting. It is characterized by an altered protein turnover in which the rate of protein degradation exceeds the rate of protein synthesis, leading to substantial [...] Read more.

Skeletal muscle atrophy is a condition associated with various physiological and pathophysiological conditions, such as denervation, cachexia, and fasting. It is characterized by an altered protein turnover in which the rate of protein degradation exceeds the rate of protein synthesis, leading to substantial muscle mass loss and weakness. Muscle protein breakdown reflects the activation of multiple proteolytic mechanisms, including lysosomal degradation, apoptosis, and ubiquitin–proteasome. Thyroid hormone (TH) plays a key role in these conditions. Indeed, skeletal muscle is among the principal TH target tissue, where TH regulates proliferation, metabolism, differentiation, homeostasis, and growth. In physiological conditions, TH stimulates both protein synthesis and degradation, and an alteration in TH levels is often responsible for a specific myopathy. Intracellular TH concentrations are modulated in skeletal muscle by a family of enzymes named deiodinases; in particular, in muscle, deiodinases type 2 (D2) and type 3 (D3) are both present. D2 activates the prohormone T4 into the active form triiodothyronine (T3), whereas D3 inactivates both T4 and T3 by the removal of an inner ring iodine. Here we will review the present knowledge of TH action in skeletal muscle atrophy, in particular, on the molecular mechanisms presiding over the control of intracellular T3 concentration in wasting muscle conditions. Finally, we will discuss the possibility of exploiting the modulation of deiodinases as a possible therapeutic approach to treat muscle atrophy. Full article

(This article belongs to the Special Issue Skeletal Muscle Atrophy and Metabolic Adaptation)

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25 pages, 1913 KiB

Open AccessReview

Metabolic Remodeling in Skeletal Muscle Atrophy as a Therapeutic Target

by Alessandra Renzini, Carles Sánchez Riera, Isidora Minic, Chiara D’Ercole, Biliana Lozanoska-Ochser, Alessia Cedola, Giuseppe Gigli, Viviana Moresi and Luca Madaro

Metabolites 2021, 11(8), 517; https://doi.org/10.3390/metabo11080517 - 5 Aug 2021

Cited by 7 | Viewed by 5632

Abstract

Skeletal muscle is a highly responsive tissue, able to remodel its size and metabolism in response to external demand. Muscle fibers can vary from fast glycolytic to slow oxidative, and their frequency in a specific muscle is tightly regulated by fiber maturation, innervation, [...] Read more.

Skeletal muscle is a highly responsive tissue, able to remodel its size and metabolism in response to external demand. Muscle fibers can vary from fast glycolytic to slow oxidative, and their frequency in a specific muscle is tightly regulated by fiber maturation, innervation, or external causes. Atrophic conditions, including aging, amyotrophic lateral sclerosis, and cancer-induced cachexia, differ in the causative factors and molecular signaling leading to muscle wasting; nevertheless, all of these conditions are characterized by metabolic remodeling, which contributes to the pathological progression of muscle atrophy. Here, we discuss how changes in muscle metabolism can be used as a therapeutic target and review the evidence in support of nutritional interventions and/or physical exercise as tools for counteracting muscle wasting in atrophic conditions. Full article

(This article belongs to the Special Issue Skeletal Muscle Atrophy and Metabolic Adaptation)

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19 pages, 1913 KiB

Open AccessReview

Altered Ca²⁺ Handling and Oxidative Stress Underlie Mitochondrial Damage and Skeletal Muscle Dysfunction in Aging and Disease

by Antonio Michelucci, Chen Liang, Feliciano Protasi and Robert T. Dirksen

Metabolites 2021, 11(7), 424; https://doi.org/10.3390/metabo11070424 - 28 Jun 2021

Cited by 32 | Viewed by 4729

Abstract

Skeletal muscle contraction relies on both high-fidelity calcium (Ca²⁺) signals and robust capacity for adenosine triphosphate (ATP) generation. Ca²⁺ release units (CRUs) are highly organized junctions between the terminal cisternae of the sarcoplasmic reticulum (SR) and the transverse tubule (T-tubule). [...] Read more.

Skeletal muscle contraction relies on both high-fidelity calcium (Ca²⁺) signals and robust capacity for adenosine triphosphate (ATP) generation. Ca²⁺ release units (CRUs) are highly organized junctions between the terminal cisternae of the sarcoplasmic reticulum (SR) and the transverse tubule (T-tubule). CRUs provide the structural framework for rapid elevations in myoplasmic Ca²⁺ during excitation–contraction (EC) coupling, the process whereby depolarization of the T-tubule membrane triggers SR Ca²⁺ release through ryanodine receptor-1 (RyR1) channels. Under conditions of local or global depletion of SR Ca²⁺ stores, store-operated Ca²⁺ entry (SOCE) provides an additional source of Ca²⁺ that originates from the extracellular space. In addition to Ca²⁺, skeletal muscle also requires ATP to both produce force and to replenish SR Ca²⁺ stores. Mitochondria are the principal intracellular organelles responsible for ATP production via aerobic respiration. This review provides a broad overview of the literature supporting a role for impaired Ca²⁺ handling, dysfunctional Ca²⁺-dependent production of reactive oxygen/nitrogen species (ROS/RNS), and structural/functional alterations in CRUs and mitochondria in the loss of muscle mass, reduction in muscle contractility, and increase in muscle damage in sarcopenia and a wide range of muscle disorders including muscular dystrophy, rhabdomyolysis, central core disease, and disuse atrophy. Understanding the impact of these processes on normal muscle function will provide important insights into potential therapeutic targets designed to prevent or reverse muscle dysfunction during aging and disease. Full article

(This article belongs to the Special Issue Skeletal Muscle Atrophy and Metabolic Adaptation)

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