Abstract
Graphical abstract
Abstract
Pathological conditions characterized by systemic inflammation and oxidative stress can often impair the muscle cells efficiency. The gradual decline of muscle mass and tone drastically reduces the motor skills of the patient affecting the simplest daily activities. Muscle dysfunction, resulting in the deterioration of muscle tissue, can lead to a serious situation of muscle wasting that can evolve into sarcopenia. In addition, muscle dysfunction causing metabolic disorders impairs the quality of life. The function of skeletal muscle is deeply conditioned by environmental, nutritional, physical, and genetic factors. Proper nutrition with balanced protein and vitamins intake and an active lifestyle helps to strengthen tissues and counteract pathological conditions and generalized weakness. Vitamin D performs antioxidant actions, indispensable in skeletal muscle. Epidemiological data indicate that vitamin D deficiency is a widespread status in the world. Vitamin D deficiency induces mitochondrial failure, reduced production of adenosine triphosphate, oxidative injury, and compromised muscle function. Among the different types of antioxidants, vitamin D has been identified as the main compound that can improve the effectiveness of the treatment for muscle weakness and improve conditions related to sarcopenia. The purpose of this review is to analyze molecular processes used by vitamin D against oxidative stress and how it can affect muscle function in order to assess whether its use as a supplement in inflammatory pathologies and oxidative stress can be useful to prevent deterioration and improve/maintain muscle function.
Introduction
Skeletal muscle is an essential tissue for important human activities such as mobility, thermogenesis, nutrition, and breathing, which guarantee survival (Rai & Demontis 2016). Skeletal muscle tissue represents 40% of our body weight and 75% of the body’s stored protein. It is a source of amino acids for the production of energy in other organs under catabolic conditions. It controls lipid metabolism and is engaged in the absorption and storage of insulin-dependent glucose. Therefore, skeletal muscle is one of the main tissues involved in metabolic activity and homeostatic balance. Following stress or nutrient deficiency, muscle mass modulation, metabolic demand, and fiber type composition are essential to balance the metabolic request of other organs that control physiological homeostasis (Blaauw et al. 2013). In addition, skeletal muscle promotes systemic responses by cytokine and myokin production. Since muscle integrity affects the homeostasis of the human body, the preservation of intact skeletal muscle mass is linked with a reduced risk of mortality (Srikanthan & Karlamangia 2014). In pathological conditions, excessive catabolism generates muscle loss and damages skeletal muscle elasticity. The exhaustion of muscle metabolic reserves, variations in the regulation of myokines, and the composition of muscle fibers promote the occurrence and evolution of different disorders (Casabona et al. 2021). The muscle mass waste is not only linked to aging (Derbré et al. 2014), atrophy and muscle weakness represent the co-morbidities of numerous pathologies such as heart, lung, and kidney failure, diabetes, neurodegenerative, dysmetabolic diseases and autoimmune disorders, infectious diseases, and tumors (Cao et al. 2018, Valle et al. 2021a, Russo et al. 2022). Therefore, all pathological conditions characterized by systemic inflammation and oxidative stress can impair muscle functionality by triggering enzymatic alterations and mitochondrial abnormalities (Patergnani et al. 2021). Muscle dysfunctions related to pathological conditions affect health status. In many subjects, skeletal muscle dysfunction may evolve into sarcopenia or cachexia, both of which are connected with increased morbidity and mortality (Rai & Demontis 2016). Adequate physiological quantity of reactive oxygen species (ROS) and reactive nitrogen species (RNS) are indispensable to normalize cellular activities and to ensure homeostasis, such as cell signaling pathways activation, regeneration, division, proliferation, and apoptosis. Oxidative stress is one of the main stress factors involved in skeletal muscle damage. It is, therefore, necessary to find an equilibrium between the quantity of ROS/RNS found in biological systems and the capability to counteract them. The amount of skeletal muscle proteins is influenced by the equilibrium between protein synthesis and breakdown of proteins, which need adenosine triphosphate (ATP). The muscle energy degree is one of the cell checkpoints between hypertrophy and protein breakdown in the course of energy stress to supply alternative energy substrates for ATP synthesis (Sartori et al. 2021). Exposure to ROS/RNS affecting Na/K-ATPase activity, calcium (Ca2+) intra-myofibrobrillar turnover, and actin-myosin kinetics generates muscle weakness. Recently it has been shown a correlation between mitochondrial atypical morphology, mitochondrial dysfunction, failure of nuclear programs mediated by ROS, and metabolites derived from mitochondria through regressive signaling to control muscle mass (Romanello & Sandri 2020). In the course of muscle wasting, mitochondrial function and, therefore, energy production are decreased (Romanello & Sandri 2020). Skeletal muscle functionality is strongly influenced by nutritional, physical, and genetic environmental factors. In vitro studies have shown a key molecular involvement of vitamin D in skeletal muscle effort and its association with muscle pain and weakness (Bollen et al. 2022). Among the many biological functions exerted by vitamin D, there is its antioxidant capacity. Vitamin D deficiency (VDD) is involved in mitochondrial dysfunction, depletion of ATP, and oxidative damage that induces muscle atrophy and consequent worsening of muscle functionality (Russo et al. 2022). To improve and restore these conditions, it seems that vitamin D successfully improves the functional state of patients and muscle weakness (Valle et al. 2023). In this review, we examine the molecular mechanisms used by vitamin D to mitigate oxidative stress and to influence muscle efficiency in order to clarify whether vitamin D supplementation can prevent muscle weakness.
ROS action on signal transduction
It is known that ROS modulate the expression of different genes of signal transduction and transcription factors engaged in inflammation, such as NF-κB, AP-1, NFAT, and HIF-1 (Poli et al. 2004). In addition, oxidants can also regulate extracellular signal-regulated kinases (ERKs) 1/2, c-Jun N-terminal kinases (JNKs), and protein kinases activated by P38 mitogen involved in cell proliferation, differentiation and apoptosis processes (Azzam et al. 2002). Particularly, NF-κB modulates the expression of genes of the immune response such as IL-6, IL-8, IL-1β, TNF-α, and several adhesion molecules (Akira & Kishimoto 1997). It is also a crucial regulator of cell proliferation, differentiation, and angiogenesis. Additionally, several kinases influence oxidative signals by activating NF-κB (Gilmore 2006). Interestingly, oxidizing/reducing agents act by inhibiting/improving DNA binding NF-κB, respectively. Among antioxidants, thioredoxins act on NF-κB in opposite ways, depending on its cellular localization. In particular, in the nucleus, thioredoxins facilitate DNA binding to NF-κB, while they block the deterioration of IκB and inhibit NF-κB activation in the cytoplasm (Hirota et al. 1999). In the immune system, among the antioxidant genes, the nuclear factor erythroid 2-related factor 2 (Nrf2) is an essential transcription and regulatory factor (Khan et al. 2019). Nrf2 plays a significant role in aging diseases, its upregulation reduces the progression of various diseases (Hybertson et al. 2011).
The impact of oxidative stress on muscle weakness
Oxidative stress arises when the generation of ROS/RNS exceeds the protective capabilities of antioxidant defense systems. This imbalance can induce cellular and molecular anomalies, culminating in tissue dysfunction. The overproduction of free radicals (ROS/RNS) can depend on various causes including alterations in cellular metabolism, the presence of environmental pollutants and certain metals, altered lifestyle habits, and cigarette smoking. Oxidative stress impinges negatively on a wide array of biological molecules and gene expression in cells. Usually, when oxidative stress occurs, compensatory antioxidant activity is established in order to restore redox balance (Dalton et al. 1999). ROS are engaged in redox signaling pathways, in which they are essential agents of various intracellular reactions. The precise physiological or pathological role of ROS hinges on factors such as their type, concentration, and production area. At low levels, ROS restrict the normal processes, comprising cell differentiation and proliferation as well as stimulation contraction. On the other hand, elevated ROS levels can significantly alter the structure and role of intracellular molecules. ROS impact genomic DNA integrity by inducing mutations and structural changes in proteins through enzymatic modification or inactivation and by altering intracellular lipids through lipid peroxidation (Sies et al. 2022). For instance, superoxide anion (O2–) reacting with nitric oxide (NO) and disabling NO creates peroxynitrite (ONOO) (Piacenza et al. 2022). This reaction can happen under conditions of elevated oxygen (O2) and NO levels, or when antioxidant activity is reduced. In the muscle, all these deleterious events can trigger myocyte dysfunction and apoptosis and cause contractile dysfunction, fibrosis, hypertrophy, and impaired muscle remodeling and lastly reduced functionality. A primary driver of oxidative stress is the presence of chronic low-grade inflammation, which is observed in numerous pathological conditions. These alterations that promote the onset of oxidative stress are not only aging but also carcinogenesis or neurodegenerative, cardiovascular, and autoimmune diseases (Warraich et al. 2020). Skeletal muscle is also a tissue affected by low-grade inflammation (Ji et al. 2022). Most inflammatory markers including IL-6, the soluble TNFα, CRP, and ROS from the local inflammatory environment circulate systemically and activate inflammatory cells, which trigger a vicious circle further releasing pro-inflammatory mediators (Andrade et al. 2022). ROS are produced not only during inflammatory processes, cellular responses to bacterial invasion, or cytokine-driven generation as a deliberate cellular defense mechanism (Grivennikova & Vinogradov 2013) but also from biological processes involving mitochondrial oxidative metabolism that consequently induce ROS release as by-products (Fig. 1). The initial product is O2, which is quickly transformed into hydrogen peroxide (H2O2) through the action of the enzyme superoxide dismutase (SOD) and then reduced to water by catalase or glutathione peroxidase (Turrens 2003). Inflammation can exert a significant impact on mitochondrial muscle function through the NO signaling pathway. Elevated levels of NO formation by inducible nitric oxide synthase (iNOS) generate a significant inhibition of the electron transport chain. This inhibition amplifies oxidative production and triggers apoptosis by permeabilizing the outer mitochondrial membrane (OMM) (Cinelli et al. 2020) (Fig. 1). The intracellular enzymes that generate ROS consist of membrane-bound NADPH oxidase (NOX), xanthine/xanthine oxidase, and the neutrophil-derived myeloperoxidase system (MPO) (Magnani & Mattevi 2019), which catalyzes the oxidation of chloride, generating a very harmful hypochlorous acid. Generally, in healthy tissues, intracellular antioxidant enzymes prevent the formation of ROS, reducing their harmful cellular effects. As already mentioned, to neutralize the disproportionate formation of intracellular ROS, there is a category of antioxidants such as glutathione (GSH) peroxidase and SOD, which contain copper–zinc–SOD and manganese–SOD (SOD1 and SOD2, respectively) (Miller 2012). GSH is one of the most important redox molecules. It acts against the toxic effects of ROS and the ratio of reduced to oxidized GSH (GSH/GSSG) is necessary for cellular defense against oxidative damage (Cantin et al. 1990). The GSH/GSSG ratio is measured after cellular stimulation to determine the state of oxidative stress within biological systems. Indeed, alterations in this data coincide with dysfunctions including inflammation, autoimmune diseases, sepsis, apoptosis, aging, and cancer. Oxidative stress can trigger cellular senescence through FOXO transcription factors and thus reduce the activity and expression of the enzyme sirtuin-1 (SIRT-1), which is linked with elevated expression of acetylation MMP-9 and NF-κB (Russo et al. 2022). In addition, ROS induces the PI3K-mTOR pathway (target of rapamycin in mammals) triggering microRNA-34a expression, which, in turn, prevents SIRT-1 expression (Barnes et al. 2019). On the whole, oxidative stress is able to influence the functions of peripheral tissues, comprising skeletal muscle tissue (Russo et al. 2022). Thus, the heightened production of ROS results in structural alterations to proteins and lipids, as well as the release of both pro-inflammatory and anti-inflammatory cytokines generating muscle atrophy and damage to muscle tissue (Gambini & Stromsnes 2022). The increased oxidative stress in skeletal muscle generates a shift toward a type IIx-oriented muscle phenotype with a limited capability to deliver and use oxygen (Russo et al. 2022) (Fig. 1).
Oxidative stress and muscle weakness. ROS from the local inflammatory activate inflammatory cells, which trigger a vicious circle further releasing pro-inflammatory mediators, including TNFα, IL-6, and CRP. The impaired antioxidant system, including GSH and SOD, does not protect from oxidative damage. Inflammation affects mitochondrial muscle function through the signaling pathway of NO and induction of apoptosis by permeabilization of OMM. Oxidative stress induces cellular senescence through activation of FOXO and reducing SIRT-1 increasing MMP-9 and NF-κB. The increased oxidative stress triggers myocyte dysfunction and apoptosis, acontractile dysfunction, fibrosis, hypertrophy, and impaired muscle remodeling with a shift toward a type IIx-oriented muscle phenotype with a reduced ability to distribute and use oxygen and reduced functionality. CRP, C reactive protein; FOXO, forkhead family of transcription factors; GSH, glutathione peroxidase; IL-6, Interleukin 6; MMP-9, matrix metallopeptidase 9; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NO, nitrogen monoxide; OMM, outer mitochondrial membrane; RNS, reactive nitrogen species; ROS, reactive oxygen species; SIRT-1, sirtuin-1; SOD, superoxide dismutase; TNFα, tumor receptor necrosis factor alpha.
Citation: Redox Experimental Medicine 2023, 1; 10.1530/REM-23-0013
The impact of mitochondria function in muscle weakness
Mitochondria are very sensitive to changes in the levels of ROS. In cases of cellular stress, the regular function of ROS is disrupted resulting in mitochondrial dysfunction, and activation of muscle autophagy and catabolic pathways (Sies et al. 2022). Efficient mitochondrial functioning is essential for maintaining the homeostasis of skeletal myocytes, as these cells heavily rely on oxidative phosphorylation (OXPHOS) for their energy requirements. The decline in cellular respiration compromises mitochondrial bioenergetics, alters mitochondrial OXPHOS, increases ROS production (Montecinos-Franjola & Ramachandran 2020), and decreases the formation of ATP. ROS induces transition pore opening of mitochondrial membrane permeability, reducing the mitochondrial reserves of β-nicotinamide adenine dinucleotide (NAD), and leading to subsequent apoptosis. Moreover, the exhaustion of mitochondrial fusion factor, OPA1, perturbs the mitochondrial system by promoting apoptosis (Montecinos-Franjola & Ramachandran 2020). In contrast, blockage of FIS1 or DRP1 constrains mitochondrial splintering and apoptosis (Romanello & Sandri 2020) (Fig. 2). As a result, unbalanced fission stimulation can lead to mitochondrial dysfunction. Mitochondrial DNA (mtDNA) is particularly vulnerable to oxidative stress, caused by a lack of histones and introns and its relatively fragile repair system compared to nuclear DNA. (Zsurka et al. 2018). Oxidative stress impairs mtDNA triggering a domino effect in which the generation of damaged subunits of the electron transport chain causes impairment of OXPHOS, reduces ATP synthesis, and triggers further generation of ROS (Wang et al. 2016). A prompt muscle failure results in protein disaggregation and failure of the antioxidant pathways. As a result, mitochondrial impairment also occurs in the course of these exacerbations. Exposure of cultured cells to sub-cytotoxic doses of H2O2 suppresses FIS1, thus inducing elongated mitochondria production with amplified oxidizing release (Russo et al. 2022). Over-regulation of fusion and/or under-regulation of fission could facilitate myocyte preservation as long as the mtDNA breaks down and, as a result, mitochondrial clumping inhibits the corrupted mitochondria clearance. In cases of tissue ischemia, changes in mitochondrial functions in atrophic peri-fascicular fibers are early events as displayed by abnormalities of SDH and myofibers deficient in COX (Cervantes-Silva et al. 2021). Consequently, mitochondrial damage leads to an intensification of ROS formation, which in turn drives the expression of type I genes induced by IFNs, fostering muscle inflammation. This chain of events can perpetuate the disease process (Russo et al. 2022, Valle et al. 2023). Histochemical assays, electron microscopy, and in situ oxigraphy displayed mitochondrial aberrations, together with an elevation in ROS formation and a decrease in respiratory activity, which was linked with a decline of physical activities induced by IFN-β. The production of ROS induced by IFN-β in human myotubes can induce mitochondrial damage. For example, in myocytes of diabetes mellitus patients, the heightened expression of both type I and type II IFN genes is linked to the expression of genes involved in inflammatory response and healing (Russo et al. 2022, Valle et al. 2023). Therefore, these findings emphasize the pivotal function of mitochondria and ROS in many clinical conditions. Inflammation affects mitochondrial muscle function. NO affects the functions of mitochondria by controlling biogenesis, O2 depletion, and homeostasis redox (Tengan & Moraes 2017). Inflammation has been shown to impair mitochondrial turnover (Zsurka, et al. 2018). TNF-α strongly stimulates iNOS and affects NO signaling, this establishes a mechanistic link between inflammation and mitochondrial impairment. Moreover, the increased formation of NO by iNOS causes inhibition of the electron transport chain, further production of oxidants, and induction of apoptosis by OMM (Boyd & Cadenas 2002). TNF-α also promotes apoptosis through the death receptor signaling pathway (Parameswaran & Patial 2010). In addition, elevated levels of TNF-α restrained the expression of PGC-1α, mitochondrial TFAM, and nuclear respiratory factor 1 in C2C12 myoblasts, and therefore inhibit mitochondriogenesis (Remels et al. 2010) (Fig. 2). For instance, in cases such as chronic obstructive pulmonary disease (COPD), it is well-documented that the inflammatory response has a substantial impact on the oxidative capacity of muscles. This is reflected in changes in citrate synthase activity, alterations in the expression of PGC-1α, and reductions in type IIa oxidative muscle fibers (Tang et al. 2013). Therefore, chronic low-grade inflammation and oxidative–antioxidant imbalance could facilitate changes in cellular phenotypes throughout the body, compromising the homeostasis of organs and tissues.
Antioxidative role of vitamin D in muscle dysfunction. Vitamin D induces the VDR in satellite and central cells, promoting their ability to self-renewal and proliferation cell differentiation. The activation of the VDR by preventing oxidative stress promotes biogenesis and mitochondrial fusion and, by reducing the consumption of oxidative stress and mitochondrial dysfunction improves the structure of mitochondrial ridges by regulating the expression of MFN1/2, OPA1, and Drp1. Vitamin D has positive effects on Sirt1 and mitochondrial function. Vitamin D supplementation induces activation of Sirt1 and AMPK in skeletal muscle cells. Vitamin D increases the expression of the precursor of irisin in muscle cells only in the presence of an intact expression of Sirt1. AMPK and Sirt1 influence the activation and transcription of PGC-1α. AMP, 5'AMP-activated protein kinase; AMPK, adenosine monophosphate (AMPK); 1,25(OH)2D3, calcitriol; Drp1, dynamin-related protein 1; IL-1β,interleukin-1 beta; MFN1/2, mitofusin; OPA1, mitochondrial dynamin like GTPase; PGC-1α, peroxisome proliferator-activated receptor-gamma coactivator; PTH, parathyroid hormone; ROS, reactive oxygen species; SIRT-1, sirtuin-1; SOD, superoxide dismutase; TNF-α, tumor receptor necrosis factor alpha; VDR, vitamin D receptor.
Citation: Redox Experimental Medicine 2023, 1; 10.1530/REM-23-0013
Biological effect of Vitamin D on skeletal muscle function
Vitamin D or calciferol is a fat-soluble pro-hormone available in two active forms: D3 (cholecalciferol) and D2 (ergocalciferol). Vitamin D can be obtained through epidermal synthesis or dietary intake. The UVB rays of sunlight penetrate the epidermis to activate the photo-isomerization of 7-dehydrocholesterol (7DHC) into vitamin D3, a reaction driven by 7-dehydrocholesterol reductase (DHCR7). Instead, vitamin D2 (ergocalciferol) comes from plant ergosterol. Mainly vitamin D is a regulator Ca2+ levels and the maintenance of skeletal health. Its shortage is linked to bone diseases such as rickets and osteoporosis (Laird et al. 2010). Additionally, vitamin D3 is an immunoregulator with extraordinary influence on the inflammatory response, muscle damage, and aerobic capacity. In recent decades, experimental evidence shows that vitamin D is engaged in skeletal muscle restoration (Valle et al. 2023). The vitamin D system is found more in the precursors of myocytes than in adult skeletal muscle (Russo et al. 2022, Valle et al. 2023) (Fig. 3). Vitamin D3 and vitamin D2 follow the same metabolic pathway for the synthesis of their biologically active form. The first metabolic phase occurs in the liver and is the transformation of D2/D3 into 25-hydroxyvitamin D (25(OH)D; calcidiol) from 25-hydroxylase (CYP2R1). Calcidiol is the main circulating form of vitamin D and is commonly used to clinically assess vitamin D status. About 85% of the circulating 25(OH)D is bound to a protein carrier, the vitamin D-binding protein (DBP), which belongs to the albumin family (Todd et al. 2015). DBP-bound 25(OH)D transfers to the kidney and is hydroxylated by 1α-hydroxylase (CYP27B1) to form the biologically active metabolite, 1α,25-dihydroxyvitamin D (1,25(OH)2D; calcitriol) in circulation. CYP27B1, in addition to various tissues, is also expressed in the muscle, allowing the local transformation of inactive into active vitamin D (Ceglia 2008). Alternatively, particularly in skeletal muscle, 25(OH)D attached to DBP enters into the target cells through the megalin–cubilin transmembrane complex (LRP2/CUBN). Within the cell, the D–DBP complex of 25(OH) binds to cytoplasmic actin. Vitamin D exerts its biological function by binding with its nuclear receptor, the vitamin D receptor (VDR). The existence of the VDR has been verified within muscle cells, providing conclusive evidence of the important influence of vitamin D on skeletal muscle function (Bischoff et al. 2001). The interaction between vitamin D to the VDR triggers the intracellular absorption of inorganic phosphates used to produce energy-rich phosphatic compounds, which are crucial for supporting muscle contractility (Russo et al. 2022). 1,25(OH)2D prompts the expression of protein 1 leading to the activation of myogenic determination factor 1 (MyoD1) and consequently inhibits the time-dependent myostatin. Moreover, vitamin D regulates the signaling pathways O Fork (FOXO) 3 and Notch promoting the self-renewal of myoblasts and supporting the satellite stem cell pool (Russo et al. 2022) (Fig. 3). The VDR in musculoskeletal tissue facilitates muscle protein synthesis and is essential to maintaining muscle volume (Russo et al. 2022, Valle et al. 2023). Active vitamin D stimulates a large amount of the VDR in satellite cells during muscle regeneration. The addition of 1,25(OH)2 in myoblasts enhances VDR expression, reduces cell proliferation, and stimulates myogenic differentiation (Garcia et al. 2001). As a result of muscle injury, the expression of VDR and CYP27B1, which during the homeostatic status is moderate, increases significantly. Musculoskeletal tissue is capable of regenerating, as a result of acute or chronic damage, thanks to the existence of adult stem cells referred to as satellite cells (Mannino et al. 2022). Satellite cells undergo asymmetric division, on the one hand, this division preserves the resident satellite cell pool and on the other hand, it ensures cellular differentiation progresses (Mannino et al. 2022). It is noteworthy that the VDR is not only expressed in muscle cells but also in satellite cells, suggesting a potential direct involvement of vitamin D in muscle regeneration (Srikuea et al. 2020). Low levels of vitamin D have been linked to symptoms such as myalgia, reduced muscle mass, weakness, and a higher chance of sarcopenia. Nevertheless, the precise role of vitamin D in promoting overall skeletal muscle health remains a subject of ongoing research and is not entirely understood.
Vitamin D and skeletal muscle. Vitamin D can be obtained through epidermal synthesis or dietary intake. Vitamin D3 and vitamin D2 follow the same metabolic pathway for the synthesis of their biologically active form. The main function of vitamin D is the regulation of Ca2+ levels and the maintenance of skeletal and muscle health, but it is also a potent immunoregulator and impacts on the inflammatory response, muscle damage, and aerobic capacity. The circulating 25(OH)D is bound to a protein carrier, the DBP. In skeletal muscle, 25(OH)D bound to DBP enters the target cells through the LRP2/CUBN transmembrane complex. Within the cell, the D-DBP complex of 25(OH) binds to cytoplasmic actin. 1,25(OH)2D induces protein 1 expression for the determination of MyoD1. Vitamin D modulates the signaling pathways of FOXO 3 promoting self-renewal of myoblasts. VDR expressed in skeletal muscle induces muscle protein synthesis and is necessary to maintain muscle volume and muscle regeneration. 1,25(OH)2D3, calcitriol; FOXO, Forkhead family of transcription factors; LRP2/CUBN, megalin–cubilin transmembrane complex; MyoD1, myogenic determination factor 1; PTH, parathyroid hormone; DBP, vitamin D- binding protein.
Citation: Redox Experimental Medicine 2023, 1; 10.1530/REM-23-0013
Molecular mechanisms of vitamin D in musculoskeletal homeostasis
It is known that vitamin D plays a fundamental role in Ca2+ homeostasis maintenance, which is controlled by parathormone (PTH) agent. PTH promotes the formation of active vitamin D that can interact with the VDR and, in turn, can promote the absorption of Ca2+ and phosphates. Vitamin D is not directly related to PTH, while it is to Ca2+. Therefore, VDD or low sun exposure can lead to an increase in PTH. Excess circulating PTH can lead to bone decompensation, causing skeletal fragility (Bienaimé et al. 2011). It has been found that vitamin D treatments in primary hyperparathyroidism (PHPT) with associated hypovitaminosis enhanced serum levels of irisin. Vitamin D is known to improve myogenic differentiation (Ainbinder et al. 2015). Recently, it has been observed a relationship between vitamin D and irisin (Wang et al. 2022). Both molecules are essential regulators of the musculoskeletal apparatus and energetic homeostasis (Fig. 4). Irisin is a γ-receptor activated by PGC-1α-dependent myokine, largely expressed by skeletal muscles and exerts beneficial roles in human health. PGC-1α affects the secretion of irisin in skeletal muscle cells. PGC-1α is a transcriptional regulator that facilitates various transcription factors to regulate an elaborate gene system (Halling & Pilegaard 2020). It controls the mitochondrial content of the tissue and in the program leads to the formation of brown adipose tissue (Cannon & Nedergaard 2004). The protein PGC-1α increases the expression of the transmembrane fibronectin protein type III, protein 5 containing domains (FNDC5), the precursor of irisin (Adamovich et al. 2013). Irisin influences macrophage and adipocyte activity in inflammatory response (Korta et al. 2019). At high levels, irisin regulates the expression of inflammatory cytokines such as IL-1β and TNF-α (Ho & Wang 2021). In addition, irisin exhibits anti-oxidative and anti-apoptotic actions in various pathological contexts, improving antioxidant enzyme formation and decreasing ROS production (Askari et al. 2018). Irisin promotes the oxidation of fatty acids (Xin et al. 2016), increases the release of glycerol molecules, and inhibits the accumulation of lipids in adipocytes by up-regulating the expression of genes involved in lipolysis such as HSL, ATGL, and FABP4 (Xiong 2015). It has been found that stimulation with vitamin D in skeletal muscle cells induces the expression of FNDC5, the precursor of irisin. The possible increase in vitamin D-dependent levels of irisin is supported by other recent preclinical studies. It was observed that rats with hypovitaminosis D were hypoirisynemic (Stavenuiter et al. 2015), and vitamin D supplementation changed the gene expression of FNDC5 in the skeletal muscle of a diabetic rat model (Nadimi et al. 2019). Previous studies demonstrated a negative relationship between irisin and vitamin D. The negative association between irisin and vitamin D has also been observed in patients with type 1 diabetes mellitus (Faienza et al. 2018) and in patients with Charcot-Marie-Tooth disease, a phenotypically inherited polyneuropathy mainly characterized by gradual distal weakness and muscle atrophy (Colaianni et al. 2022). Treatment with vitamin D induces activation of Sirt1 and adenosine monophosphate (AMPK) in skeletal muscle cells (Chang 2019). Vitamin D promotes the expression of irisin precursor in muscle cells merely if occurs an integral expression of Sirt1 (Fig. 4). Sirt1 is an NAD-dependent protein diacetylase. Sirtuin 1 (Cantó et al. 2010) capable of exerting activation of AMPK (Chang 2019). Being the main regulators of the oxidative capacity of muscle fiber and mitochondrial biogenesis, AMPK and Sirt1 impact the activation and transcription of PGC-1α (Russo et al. 2022, Valle et al. 2023) (Fig. 4).
Vitamin D in musculoskeletal homeostasis. Vitamin D is widely involved in the maintenance of Ca2+homeostasis, which is controlled by PTH, which in turn promotes Ca2+ retention in the kidney and promotes the formation of active vitamin D that interacting with the VDR promotes the absorption of Ca2+ and phosphates. VDD or low sun exposure can lead to an increase in PTH which leads to skeletal fragility. Levels of 25(OH)D3 below 25 nmol/L cause a decreased production of ATP, increased production of ROS, and mitochondrial dysfunction. Vitamin D supplementation in primary hyperparathyroidism increases serum levels of irisin. Both vitamin D and irisin regulate the musculoskeletal system and energetic homeostasis. Vitamin D in skeletal muscle cells induces the expression of FNDC5, the precursor of irisin. Irisin exerts anti-apoptotic actions and anti-oxidative activity decreasing the production of ROS improving the production of antioxidant enzymes. PGC-1α expression affects the secretion of irisin in skeletal muscle cells. Vitamin D represses FOXO1 and induces the inhibition of atrogin-1 and the expression MuRF1. Vitamin D supplementation activates the VDR and induces the antioxidant Nrf2-Keap1 pathway. ATP, adenosine triphosphate; 1,25(OH)2D3, calcitriol; FNDC5, protein 5 containing domains; FOXO, Forkhead family of transcription factors; Keap1, kelch-like ECH-associated protein 1; MuRF1,muscle RINGfinger protein-1; Nrf-1, nuclear factor erythroid 2-related factor 2; PTH, parathyroid hormone; PGC-1α, peroxisome proliferator-activated receptor-gamma coactivator; RNS, reactive nitrogen species; ROS, reactive oxygen species; VDD, vitamin D deficiency; VDR, vitamin D receptor.
Citation: Redox Experimental Medicine 2023, 1; 10.1530/REM-23-0013
Vitamin D deficiency and muscle dysfunction
VDD is widespread in the world population (Wiciński et al. 2019). It occurs when levels of 25(OH)D3 decrease below 25 nmol/L. VDD causes a reduction of ATP and enhances ROS formation and mitochondrial dysfunction (Wimalawansa 2019). Numerous studies have shown that VDD causes a reduction in muscle function and raises the incidence of muscle weakness and wasting (Prokopidis et al. 2022). Among the many causes, aging increases the risk of VDD not only due to poor nutrition but also due to the reduced ability to synthesize vitamin D resulting in decreased expression of VDR in skeletal muscle (Russo et al. 2022, Valle et al. 2023) or reduced expression of vitamin D metabolic enzymes. Subjects with VDD show a change in the type of muscle fiber. Usually, type I is characterized by slow contraction time and low resistance generation lasting for hours, while type II is characterized by rapid contraction time and high resistance generation, but lasting minutes of resistance. Moreover, type II fibers are responsible for the prevention of falls, and the number of type II fiber changes with the raising of type I fibers. In muscle biopsies of VDD subjects has been detected muscle wasting (typically atrophy of type II fibers), large interfibrillar spaces, and fat infiltration within the muscle (Ceglia et al. 2013) typical of the elderly (Fig. 4). It was observed that vitamin D unaltered the relative proportion of type II fibers and there was also no substantial variance in muscle extension power and physical performance (Ceglia et al. 2013). Instead, other investigators showed changes in the area of type I and II muscle fibers after vitamin D treatment compared to the placebo group. Other studies have confirmed that treatment with vitamin D3 affects muscle function in the elderly (Pfeifer et al. 2009), improving muscle strength and balance and reducing the probability of falling in the elderly with VDD (Russo et al. 2022, Valle et al. 2023). In cellular models, the treatment of vitamin D induces the inhibition of atrogin-1 and the expression of MuRF1, while an increase in FOXO1, which is a biomarker of cachexia has been reported (Hirose et al. 2018) (Fig. 4). In addition, in an in vivo model, VDD reduced SIRT-1 activation, a protein kinase modulator activated by AMPK. In vivo studies report that after treatment with vitamin D, muscle development and function improved (Endo et al. 2003) (Fig. 4). The intramuscular vitamin D supplementation through muscle regeneration also improved the levels of VDR protein (Srikuea et al. 2020). The VDR is present in both type I and type II fibers, thus evaluating the expression and functionality of the VDR is useful. It has been found that polymorphisms in the VDR gene may affect muscle performance, but the interaction mechanisms involved are still unknown (Russo et al. 2022, Valle et al. 2023). Moreover, the VDR polymorphism affects vitamin D on muscle dysfunction in the elderly. The reduced expression of VDR caused by age contributes to the reduction of muscle strength (Russo et al. 2022, Valle et al. 2023). VDR knock-out mice present not only muscle weakness, atrophy in muscle fibers, and hypernuclearity (Russo et al. 2022) but also an irregular expression of myogenic transcription factors.
Antioxidative effect of vitamin D in muscle dysfunction
Vitamin D plays a central role in the protection of cells and tissues through the reduction of oxidative stress (Valle et al. 2021b ). The interaction between vitamin D, its receptor and ROS signaling is complex. It has already been mentioned that vitamin D regulates Ca2+ homeostasis in both skeletal muscle and mitochondria. Ca2+ is an important element for muscle energy metabolism as it interplays between mitochondria and cytosol (Rossi et al. 2019). In dysfunctional mitochondria intracellular level of Ca2+ greatly rises (Modesti et al. 2021). VDD exerts adverse effects on protein synthesis. The main proteolytic pathways in skeletal muscle are the ATP-ubiquitin-dependent system, the Ca2+-activated cytosolic system, and the lysosomal system. Should be noted that the ATP-ubiquitin-dependent system is the only one reliant on vitamin D (van der Meijden et al. 2016). Therefore, VDD may cause insufficient levels of mitochondrial Ca2+, resulting in disturbances of cellular metabolic homeostasis (Latham et al. 2021). 1α,25(OH)2D3 is beneficial in the management of muscle weakness (Ryan et al. 2016). This active form protects muscles against the damage being helpful in the regulation of tone and contraction of skeletal muscles and in muscle recovery (Latham et al. 2021). VDD modifies the kinetics of muscle contraction by reducing Ca2+ re-uptake in the sarcoplasmic reticulum, thus resulting in the maintenance of the relaxation phase of muscle contraction. VDD increasing ROS-mediated cytotoxicity could be linked with mitochondrial respiration failure (Russo et al. 2022). Therefore, VDD can contribute to exacerbate muscle damage and atrophy due to excessive mitochondrial ROS production (Latham et al. 2021), oxidative impairment, and ATP reduction. Clinical evidence indicated that muscle atrophy and deficits in muscle strength occur at low dosages of 25(OH)D (<50 nmol/L) (Bhat & Ismail 2015). In muscles, one of the reasons for the wasting results from disproportionate protein degradation and synthesis rates (Valle et al. 2021a ). In addition, VDD influences alterations in antioxidant enzyme activities (Latham et al. 2021). In skeletal muscle, VDD has an impact on nitrosative stress, protein, and lipid peroxidation and a decline of antioxidant enzyme activity (Russo et al. 2022). Indeed, C2C12 cell line 1,25(OH) D-treated exhibited a reduction of ROS synthesis, protein ubiquitination, protein and lipid oxidation, intracellular impairment, muscle proteolysis, and lastly atrophy. Instead, in the paraspinal muscle 1,25(OH)D intensifies the activity of glutathione peroxidase (GPx), SOD and mitochondrial biogenesis markers (van der Meijden et al. 2016). VDD subjects 1α,25(OH)2D3 supplementation raises the rate of mitochondrial oxidative phosphorylation (Bhat & Ismail 2015). In skeletal muscle cells, 1α,25(OH)2D3 stimulation enhances oxygen consumption rate (OCR) and ATP generation (Ryan et al. 2016). The state of vitamin D determines changes in the mitochondrial dynamics of skeletal muscle, the phosphorylation of pyruvate dehydrogenase and the expression of nuclear genes encoding mitochondrial proteins and affecting the performance of skeletal muscle (Seldeen et al. 2020). Nevertheless, another investigation showed that 1α,25(OH)2D3 did not induce an increase in OCR in mitochondria. Thus, it is possible that the effects of 1α,25(OH)2D3 on OCR could be VDR dependent (Bhat & Ismail 2015). Following an injury, myocytes need optimal ROS levels for signal transduction. Excessive ROS formation generated by disabling defensive antioxidant systems, compromises tissue muscle health. An increase in body weight was observed in animals subjected to hyper-exposure (Russo et al. 2022). Experimental studies proved that vitamin D deprivation for 12 months in mice caused decreased anaerobic capacity, lean mass, and gait instabilities, a susceptibility toward a smaller cross-section area of fast-shrinking fibers and sarcopenia. In addition, VDD mice increased atrogin-1 gene expression associated with atrophy and a different expression of mir-26a associated with muscle regulation compared with control mice (Ke et al. 2016). Rats treated with vitamin D showed a decrease in both oxidative stress and tissue impairment after full exercise (Ke et al. 2016). Some investigations showed that vitamin D analogs preserve skeletal muscle and cells suffering from oxidative stress (Srikuea et al. 2020), confirming that vitamin D is essential for mitochondrial function and oxidative stress in skeletal muscle. The explanation of the mechanism by which vitamin D regulates oxidative stress may depend on its effect on the regulation of mitochondrial activity and dynamism. Nrf-2 is an essential transcription factor intervening in antioxidant defense pathways (Chen et al. 2019). The downregulation of Nrf-2 generates the collapse of the antioxidant defense system (Xiang et al. 2021). Vitamin D supplementation activates the VDR (Mathyssen et al. 2020) and elicits the antioxidant Nrf2-Keap1 pathway (Chen et al. 2019) (Fig. 4).
Vitamin D regulation on mitochondrial functionality
As mentioned previously, pro-inflammatory cytokines IL6, TNF-α, and protein C-reactive plasma levels increase and negatively affect mitochondrial muscle activity (De la Fuente & Miquel et al. 2009). Inflammation preventing autophagy could intensify mitochondrial dysfunction (Rosa et al. 2016). Mitochondria are skilled in releasing superoxide anion. Their biogenesis is regulated by PGC-1α. This transcriptional coactivator controls oxidative stress and stimulates mitochondrial biogenesis that can facilitate the muscle tissue reshaping to a fiber-like structure with metabolic characteristics that promote oxidation to glycolysis (St-Pierre et al. 2006). Mitochondria take part in the progression of atrophy (Salles et al. 2013). Increased PGC-1α causes an inhibition of the transcriptional activity of FOXO3a. FOXO3a belongs to regulatory factors of various atrophy-related genes known as ‘atrophy patterns’. Usually, these factors are expressed in the course of atrophy. They promote the expression of many genes and facilitate protein degradation (Sandri et al. 2004). In addition, FOXO prevents cell cycle progression and triggers apoptosis (Tran et al. 2003). VDD decreases PGC-1α and IGF-1 through the nuclear VDR. An experimental study showed that the C2C12 cell line treatment with vitamin D improved VDR signaling and inhibited the nuclear expression, activity, and translocation of FOXO1. Inhibition of FOXO1 activity declined when the VDR was repressed. Hence, FOXO1 is a valuable regulator of VDR signaling in the course of skeletal muscle atrophy (Chen et al. 2016). As well, Akt plays a significant role in the evolution of muscle atrophy (Kitajima et al. 2020). The action of FOXO3 is inhibited by Akt which, by phosphorylation of the residues well-maintained by FOXO3, causes its inactivation and impairs its action toward the target genes (Kitajima et al. 2020). FOXO3a, if it is phosphorylated, fails to translocate into the nucleus, which does not allow the expression of target genes for muscle atrophy, including F-box (MAFbx) and Murf proteins. the signaling pathway promoting MuRF1 and MAFbx expression is mediated by Src-ERK1/2-Akt-FOXO (Saline et al. 2019). Moreover, Akt modulates muscle synthesis via mTOR. In an experimental model of mouse skeletal myostatic tubes, 1α,25(OH)2D3 induces the Akt/mTOR-dependent pathway, enabling the activation of their protein synthesis (Salles et al. 2013). Further, sirtuin-1 is a regulator of inflammation, oxidative stress, mitochondrial activity, biogenesis, cellular senescence, and apoptosis. Catalyzed deacetylation by SIRT-1 promotes FOXO activity and DNA binding affinity (An et al. 2010). Vitamin D induces SIRT-1 expression (Russo et al. 2022) exerting positive effects on Sirt1 protein and mitochondrial activity (Fig. 2). Further, the VDR regulates FOXO protein function and operates regulating selectively SIRT-1, which, in turn, regulates VDR signaling (Russo et al. 2022). During muscle regeneration, the 1,25(OH)2D3–VDR complex in satellite cells and the central nuclei of the myocardium, supports their capacity for cell proliferation, self-renewal, and differentiation. The VDR activation by preventing oxidative stress stimulates biogenesis and mitochondrial fusion. Moreover, VDR activation by decreasing the consumption of oxidative stress and mitochondrial dysfunction facilitates the restoration of mitochondrial ridges through the modulation of MFN1/2, OPA1, and Drp1 expression (Fig. 2). In conclusion, VDD impedes VDR signaling, induces oxidative stress, and decreases biogenesis and mitochondrial activity. Hence, a permanent VDD exerts a detrimental impact on mitochondrial function leading to muscle atrophy.
Conclusion and perspectives
In addition to diseases associated with low-grade inflammation, excessive production of ROS/RNS can produce muscle dysfunction. Oxidative stress causes significant cellular phenotypic changes including apoptosis and autophagy. Oxidative stress is followed by other changes, including the decline of the anti-oxidative system, abnormal steroid synthesis, and mitochondrial damage. The exact mechanism of oxidative stress still needs further study. Recent investigations have shown that signaling pathways such as PI3K/AKT, MAPK, FOXO, and Nrf2/KEAP1 axes, as well as the inflammatory signaling pathway and mitophagy, are included in the management of oxidative stress. Other studies suggest that vitamin D can relieve muscle dysfunction by acting in these signaling pathways and thus inhibiting oxidative stress. However, the analyses on the value of vitamin D are still, sometimes, contradictory, therefore further experiments and clinical data are needed to supply additional information to demonstrate the effectiveness of vitamin D focused on oxidative stress and confirm its clinical application. We hope this review will give new ideas and suggestions for further experimental studies and dietary protocols.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This research was funded by PNRR: ‘Health Extended Alliance for Innovative Therapies, Advanced Lab-research, and Integrated Approaches of Precision’ CUP: E63C22002080006.
Author contribution statement
CR and MSV contributed equally to this manuscript through conceptualization and literature research. L.M. supervised and edited the manuscript. All authors approved the submitted version. All authors have read and agreed to the published version of the manuscript.
Acknowledgements
The authors wish to thank the Scientific Bureau of the University of Catania for language support.
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