bims-moremu 2024-09-01 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2024–09–01
34 papers selected by
Anna Vainshtein, Craft Science Inc.

TRIM16 facilitates SIRT-1-dependent regulation of antioxidant response to alleviate age-related sarcopenia.
The Hox-based positional memory in muscle stem cells.
Skeletal muscle myosin heavy chain fragmentation as a potential marker of protein degradation in response to resistance training and disuse atrophy.
The role of ZEB1 in mediating the protective effects of metformin on skeletal muscle atrophy.
Exercise-induced Nrf2 activation increases antioxidant defenses in skeletal muscles.
Inducible deletion of endothelial cell Efnb2 delays capillary regeneration and attenuates myofibre reinnervation following myotoxin injury in mice.
Combination of transcriptomics and proteomics for analyzing potential biomarker and molecular mechanism underlying skeletal muscle atrophy.
Enhanced ECCD36 Signaling Promotes Skeletal Muscle Insulin Resistance in Female Mice.
Constitutive, Muscle-Specific Orai1 Knockout Results in the Incomplete Assembly of Ca2+ Entry Units and a Reduction in the Age-Dependent Formation of Tubular Aggregates.
Force-induced dephosphorylation activates the cochaperone BAG3 to coordinate protein homeostasis and membrane traffic.
Paternal exercise induces antioxidant defenses by α-Klotho/Keap1 pathways in the skeletal muscle of offspring exposed to a high fat-diet without changing telomere length.
Does AMPK bind glycogen in skeletal muscle or is the relationship correlative?
Mitohormesis during advanced stages of Duchenne muscular dystrophy reveals a redox-sensitive creatine pathway that can be enhanced by the mitochondrial-targeting peptide SBT-20.
CaMKII protein expression and phosphorylation in human skeletal muscle by immunoblotting: isoform specificity.
Loss of mitochondria long-chain fatty acid oxidation impairs skeletal muscle contractility by disrupting myofibril structure and calcium homeostasis.
An atlas of caspase cleavage events in differentiating muscle cells.
CaV1.1 voltage-sensing domain III exclusively controls skeletal muscle excitation-contraction coupling.
Single-Nucleus RNA Sequencing Unravels Early Mechanisms of Human Becker Muscular Dystrophy.
Senescent cells inhibit mouse myoblast differentiation via the SASP-lipid 15d-PGJ2 mediated modification and control of HRas.
Progression of total training volume in resistance training studies and its application to skeletal muscle growth.
Dietary Protein and Physical Exercise for the Treatment of Sarcopenia.
Metabolic small talk during exercise: The role of metabokines and lipokines in interorgan signalling.
Hydrogen sulfide inhibits skeletal muscle ageing by up-regulating autophagy through promoting deubiquitination of adenosine 5'-monophosphate (AMP)-activated protein kinase α1 via ubiquitin specific peptidase 5.
Caveolin and NOS in the Development of Muscular Dystrophy.
Chikungunya and Mayaro Viruses Induce Chronic Skeletal Muscle Atrophy Triggered by Pro-Inflammatory and Oxidative Response.
Increased Homer Activity and NMJ Localization in the Vestibular Lesion het-/- Mouse soleus Muscle.
Ubiquitination Insight from Spinal Muscular Atrophy-From Pathogenesis to Therapy: A Muscle Perspective.
Spatiotemporal transcriptomic mapping of regenerative inflammation in skeletal muscle reveals a dynamic multilayered tissue architecture.
Identification of the molecular link: STAT3 is a shared key gene linking postmenopausal osteoporosis and sarcopenia.
Betaine delays age-related muscle loss by mitigating Mss51-induced impairment in mitochondrial respiration via Yin Yang1.
N-acetylcysteine stimulates the proliferation and differentiation in heat-stressed skeletal muscle cells.
Hormones, Hypertrophy, and Hype: An Evidence-guided Primer on Endogenous Endocrine Influences on Exercise-Induced Muscle Hypertrophy.
Serum proteomic profiling of physical activity reveals CD300LG as a novel exerkine with a potential causal link to glucose homeostasis.
Targeting organ-specific mitochondrial dysfunction to improve biological aging.

J Cachexia Sarcopenia Muscle. 2024 Aug 27.

TRIM16 facilitates SIRT-1-dependent regulation of antioxidant response to alleviate age-related sarcopenia.

Ai Guo, Ke Huang, Quanyi Lu, Bailong Tao, Kai Li, Dianming Jiang.

   BACKGROUND: Age-related sarcopenia, characterized by reduced skeletal muscle mass and function, significantly affects the health of the elderly individuals. Oxidative stress plays a crucial role in the development of sarcopenia. Tripartite motif containing 16 (TRIM16) is implicated in orchestrating antioxidant responses to mitigate oxidative stress, yet its regulatory role in skeletal muscle remains unclear. This study aims to elucidate the impact of TRIM16 on enhancing antioxidant response through SIRT-1, consequently mitigating age-related oxidative stress, and ameliorating muscle atrophy.
METHODS: Aged mouse models were established utilizing male mice at 18 months with D-galactose (D-gal, 200 mg/kg) intervention and at 24 months with natural aging, while 3-month-old young mice served as controls. Muscle cell senescence was induced in C2C12 myoblasts using 30 g/L D-gal. TRIM16 was overexpressed in the skeletal muscle of aged mice and silenced/overexpressed in C2C12 myoblasts. The effects of TRIM16 on skeletal muscle mass, grip strength, morphological changes, myotube formation, myogenic differentiation, and muscle atrophy indicators were evaluated. Reactive oxygen species (ROS) levels and oxidative stress-related parameters were measured. The SIRT-1 inhibitor EX-527 was employed to elucidate the protective role of TRIM16 mediated through SIRT-1.
RESULTS: Aged mice displayed significant reductions in lean mass (-11.58%; -14.47% vs. young, P < 0.05), hindlimb lean mass (-17.38%; -15.95% vs. young, P < 0.05), and grip strength (-22.29%; -31.45% vs. young, P < 0.01). Skeletal muscle fibre cross-sectional area (CSA) decreased (-29.30%; -24.12% vs. young, P < 0.05). TRIM16 expression significantly decreased in aging skeletal muscle (-56.82%; -66.27% vs. young, P < 0.001) and senescent muscle cells (-46.53% vs. control, P < 0.001). ROS levels increased (+69.83% vs. control, P < 0.001), and myotube formation decreased in senescent muscle cells (-56.68% vs. control, P < 0.001). Expression of myogenic differentiation and antioxidant indicators decreased, while muscle atrophy markers increased in vivo and in vitro (all P < 0.05). Silencing TRIM16 in myoblasts induced oxidative stress and myotube atrophy, while TRIM16 overexpression partially mitigated aging effects on skeletal muscle. TRIM16 activation enhanced SIRT-1 expression (+75.38% vs. control, P < 0.001). SIRT-1 inhibitor EX-527 (100 μM) suppressed TRIM16's antioxidant response and mitigating muscle atrophy, offsetting the protective effect of TRIM16 on senescent muscle cells.
CONCLUSIONS: This study elucidates TRIM16's role in mitigating oxidative stress and ameliorating muscle atrophy through the activation of SIRT-1-dependent antioxidant effects. TRIM16 emerges as a potential therapeutic target for age-related sarcopenia.

Keywords:  Muscle atrophy; Oxidative stress; Sarcopenia; TRIM16

DOI:  https://doi.org/10.1002/jcsm.13553
J Biochem. 2024 Aug 28. pii: mvae059. [Epub ahead of print]

The Hox-based positional memory in muscle stem cells.

Ryosuke Okino, Yuki Goda, Yusuke Ono.

  The skeletal muscle is a contractile tissue distributed throughout the body with various anatomical sizes, shapes, and functions. In pathological conditions, such as muscular dystrophy, age-related sarcopenia, and cancer cachexia, skeletal muscles are not uniformly affected throughout the body. This region-specific vulnerability cannot be fully explained by known physiological classifications, including muscle fiber types. Accumulating evidence indicates that the expression patterns of topographic homeobox (Hox) genes provide a molecular signature of positional memory, reflecting the anatomical locations and embryonic history of muscles and their associated muscle stem cells in adult mice and humans. Hox-based positional memory is not merely a remnant of embryonic development but is expected to be an intrinsic determinant controlling muscle function because recent studies have shown that aberrant Hox genes affect muscle stem cells. In this review, we discuss the concept of Hox-based positional memory, which may offer a new perspective on the region-specific pathophysiology of muscle disorders.

Keywords:  Hox; muscle regeneration; muscle stem cells; positional memory; skeletal muscle

DOI:  https://doi.org/10.1093/jb/mvae059
Exp Physiol. 2024 Aug 24.

Skeletal muscle myosin heavy chain fragmentation as a potential marker of protein degradation in response to resistance training and disuse atrophy.

Daniel L Plotkin, Madison L Mattingly, Derick A Anglin, J Max Michel, Joshua S Godwin, Mason C McIntosh, Nicholas J Kontos, João G A Bergamasco, Maíra C Scarpelli, Vitor Angleri, Lemuel W Taylor, Darryn S Willoughby, C Brooks Mobley, Andreas N Kavazis, Carlos Ugrinowitsch, Cleiton A Libardi, Michael D Roberts.

  We examined how resistance exercise (RE), cycling exercise and disuse atrophy affect myosin heavy chain (MyHC) protein fragmentation. The 1boutRE study involved younger men (n = 8; 5 ± 2 years of RE experience) performing a lower body RE bout with vastus lateralis (VL) biopsies being obtained prior to and acutely following exercise. With the 10weekRT study, VL biopsies were obtained in 36 younger adults before and 24 h after their first/naïve RE bout. Participants also engaged in 10 weeks of resistance training and donated VL biopsies before and 24 h after their last RE bout. VL biopsies were also examined in an acute cycling study (n = 7) and a study involving 2 weeks of leg immobilization (n = 20). In the 1boutRE study, fragmentation of all MyHC isoforms (MyHCTotal) increased 3 h post-RE (∼200%, P = 0.018) and returned to pre-exercise levels by 6 h post-RE. Interestingly, a greater magnitude increase in MyHC type IIa versus I isoform fragmentation occurred 3 h post-RE (8.6 ± 6.3-fold vs. 2.1 ± 0.7-fold, P = 0.018). In 10weekRT participants, the first/naïve and last RE bouts increased MyHCTotal fragmentation 24 h post-RE (+65% and +36%, P < 0.001); however, the last RE bout response was attenuated compared to the first bout (P = 0.045). Although cycling exercise did not alter MyHCTotal fragmentation, ∼8% VL atrophy with 2 weeks of leg immobilization increased MyHCTotal fragmentation (∼108%, P < 0.001). Mechanistic C2C12 myotube experiments indicated that MyHCTotal fragmentation is likely due to calpain proteases. In summary, RE and disuse atrophy increase MyHC protein fragmentation. Research into how ageing and disease-associated muscle atrophy affect these outcomes is needed. HIGHLIGHTS: What is the central question of this study? How different exercise stressors and disuse affect skeletal muscle myosin heavy chain fragmentation. What is the main finding and its importance? This investigation is the first to demonstrate that resistance exercise and disuse atrophy lead to skeletal muscle myosin heavy chain protein fragmentation in humans. Mechanistic in vitro experiments provide additional evidence that MyHC fragmentation occurs through calpain proteases.

Keywords:  immunoblotting; myosin heavy chain; proteolysis; resistance exercise; skeletal muscle

DOI:  https://doi.org/10.1113/EP092093
J Pharmacol Sci. 2024 Oct;pii: S1347-8613(24)00049-5. [Epub ahead of print]156(2): 57-68

The role of ZEB1 in mediating the protective effects of metformin on skeletal muscle atrophy.

Peiyu Jia, Ji Che, Xiaoting Xie, Qi Han, Yantao Ma, Yong Guo, Yongjun Zheng.

  Metformin is an important antidiabetic drug that has the potential to reduce skeletal muscle atrophy and promote the differentiation of muscle cells. However, the exact molecular mechanism underlying these functions remains unclear. Previous studies revealed that the transcription factor zinc finger E-box-binding homeobox 1 (ZEB1), which participates in tumor progression, inhibits muscle atrophy. Therefore, we hypothesized that the protective effect of metformin might be related to ZEB1. We investigated the positive effect of metformin on IL-1β-induced skeletal muscle atrophy by regulating ZEB1 in vitro and in vivo. Compared with the normal cell differentiation group, the metformin-treated group presented increased myotube diameters and reduced expression levels of atrophy-marker proteins. Moreover, muscle cell differentiation was hindered, when we artificially interfered with ZEB1 expression in mouse skeletal myoblast (C2C12) cells via ZEB1-specific small interfering RNA (si-ZEB1). In response to inflammatory stimulation, metformin treatment increased the expression levels of ZEB1 and three differentiation proteins, MHC, MyoD, and myogenin, whereas si-ZEB1 partially counteracted these effects. Moreover, marked atrophy was induced in a mouse model via the administration of lipopolysaccharide (LPS) to the skeletal muscles of the lower limbs. Over a 4-week period of intragastric administration, metformin treatment ameliorated muscle atrophy and increased the expression levels of ZEB1. Metformin treatment partially alleviated muscle atrophy and stimulated differentiation. Overall, our findings may provide a better understanding of the mechanism underlying the effects of metformin treatment on skeletal muscle atrophy and suggest the potential of metformin as a therapeutic drug.

Keywords:  Metformin; Muscle atrophy; Myocyte differentiation; ZEB1

DOI:  https://doi.org/10.1016/j.jphs.2024.07.004
Free Radic Biol Med. 2024 Aug 22. pii: S0891-5849(24)00590-2. [Epub ahead of print]

Exercise-induced Nrf2 activation increases antioxidant defenses in skeletal muscles.

Scott K Powers, Ronette Lategan-Potgieter, Erica Goldstein.

  Following the discovery that exercise increases the production of reactive oxygen species in contracting skeletal muscles, evidence quickly emerged that endurance exercise training increases the abundance of key antioxidant enzymes in the trained muscles. Since these early observations, knowledge about the impact that regular exercise has on skeletal muscle antioxidant capacity has increased significantly. Importantly, in recent years, our understanding of the cell signaling pathways responsible for this exercise-induced increase in antioxidant enzymes has expanded exponentially. Therefore, the goals of this review are: 1) summarize our knowledge about the influence that exercise training has on the abundance of key antioxidant enzymes in skeletal muscles; and 2) to provide a state-of-the-art review of the nuclear factor erythroid 2-related factor (Nrf2) signaling pathway that is responsible for many of the exercise-induced changes in muscle antioxidant capacity. We begin with a discussion of the sources of reactive oxygen species in contracting muscles and then examine the exercise-induced changes in the antioxidant enzymes that eliminate both superoxide radicals and hydrogen peroxide in muscle fibers. We conclude with a discussion of the advances in our understanding of the exercise-induced control of the Nrf2 signaling pathway that is responsible for the expression of numerous antioxidant proteins. In hopes of stimulating future research, we also identify gaps in our knowledge about the signaling pathways responsible for the exercise-induced increases in muscle antioxidant enzymes.

Keywords:  cell signaling; endurance exercise; oxidative stress; reactive oxygen species

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.07.041
J Physiol. 2024 Aug 28.

Inducible deletion of endothelial cell Efnb2 delays capillary regeneration and attenuates myofibre reinnervation following myotoxin injury in mice.

Aaron B Morton, Nicole L Jacobsen, Alexandra R Diller, Jacob A Kendra, Shadi Golpasandi, D D W Cornelison, Steven S Segal.

  Acute injury of skeletal muscle disrupts myofibres, microvessels and motor innervation. Myofibre regeneration is well characterized, however its relationship with the regeneration of microvessels and motor nerves is undefined. Endothelial cell (EC) ephrin-B2 (Efnb2) is required for angiogenesis during embryonic development and promotes neurovascular regeneration in the adult. We hypothesized that, following acute injury to skeletal muscle, loss of EC Efnb2 would impair microvascular regeneration and the recovery of neuromuscular junction (NMJ) integrity. Mice (aged 3-6 months) were bred for EC-specific conditional knockout (CKO) of Efnb2 following tamoxifen injection with non-injected CKO mice as controls (CON). The gluteus maximus, tibialis anterior or extensor digitorum longus muscle was then injured with local injection of BaCl2. Intravascular staining with wheat germ agglutinin revealed diminished capillary area in the gluteus maximus of CKO vs. CON at 5 days post-injury (dpi); both recovered to uninjured (0 dpi) level by 10 dpi. At 0 dpi, tibialis anterior isometric force of CKO was less than CON. At 10 dpi, isometric force was reduced by half in both groups. During intermittent contractions (75 Hz, 330 ms s-1, 120 s), isometric force fell during indirect (sciatic nerve) stimulation whereas force was maintained during direct (electrical field) stimulation of myofibres. Neuromuscular transmission failure correlated with perturbed presynaptic (terminal Schwann cells) and postsynaptic (nicotinic acetylcholine receptors) NMJ morphology in CKO. Resident satellite cell number on extensor digitorum longus myofibres did not differ between groups. Following acute injury of skeletal muscle, loss of Efnb2 in ECs delays capillary regeneration and attenuates recovery of NMJ structure and function. KEY POINTS: The relationship between microvascular regeneration and motor nerve regeneration following skeletal muscle injury is undefined. Expression of Efnb2 in endothelial cells (ECs) is essential to vascular development and promotes neurovascular regeneration in the adult. To test the hypothesis that EfnB2 in ECs is required for microvascular regeneration and myofibre reinnervation, we induced conditional knockout of Efnb2 in ECs of mice. Acute injury was then induced by BaCl2 injection into gluteus maximus, tibialis anterior or extensor digitorum longus (EDL) muscle. Capillary regeneration was reduced at 5 days post-injury (dpi) in gluteus maximus of conditional knockout vs. controls; at 10 dpi, neither differed from uninjured. Nerve stimulation revealed neuromuscular transmission failure in tibialis anterior with perturbed neuromuscular junction structure. Resident satellite cell number on EDL myofibres did not differ between groups. Conditional knockout of EC Efnb2 delays capillary regeneration and attenuates recovery of neuromuscular junction structure and function.

Keywords:  Schwann cells; angiogenesis; ephrin‐B2; microcirculation; neuromuscular junction; neuromuscular transmission failure

DOI:  https://doi.org/10.1113/JP285402
J Proteomics. 2024 Aug 22. pii: S1874-3919(24)00215-X. [Epub ahead of print]309 105283

Combination of transcriptomics and proteomics for analyzing potential biomarker and molecular mechanism underlying skeletal muscle atrophy.

Lin Yin, Shasha Wu, Peirong Bai, Xuena Wang.

   BACKGROUND: The skeletal muscle atrophy is prevalently occurred in numerous chronic disease complications. Despite its important clinical significance, there are currently no therapeutic drugs, so new biomarkers and molecular mechanisms need to be discovered urgently.
METHODS: Transcriptome and proteome sequencing data were collected from normal and skeletal muscle atrophic mice. The differentially expressed genes (DEGs) and proteins (DEPs) were analyzed. Applying PPI analysis to obtain overlapping genes and proteins, which were next subjected to GO and KEGG enrichment analysis. Combined analysis of transcriptomics and proteomics was performed to get key genes that were simultaneously found in GO and KEGG enrichment results. Subsequently, RT-qPCR and immunofluorescence were constructed to verify the expression of screened key genes.
RESULTS: By combination of transcriptomics, proteomics and RT-qPCR results, we identified 14 key genes (Cav1, Col3a1, Dnaja1, Postn, Ptges3, Cd44, Clec3b, Igfbp6, Lamc1, Alb, Itga6, Mmp2, Timp2 and Cd9) that were markedly different in atrophic mice. Single-gene GSEA and immunofluorescence suggested Cd9 was probably the biomarker for skeletal muscle atrophy.
CONCLUSIONS: Our study hinted that Cd9 was potential biomarker and may interfere with skeletal muscle atrophy through process of aerobic respiration, oxidative phosphorylation, and metabolism of amino acids and fatty acids.
SIGNIFICANCE: The present study holds the subsequent significance: Frist, we investigated biomarkers for skeletal muscle atrophy using multi-omics approach. A total of 14 genes were markedly different in skeletal muscle atrophic mice. We finally found Cd9 is a potential biomarker for skeletal muscle atrophy. Our work presents novel biomarkers and potential regulatory mechanisms for the early detection and intervention of muscle atrophy.

Keywords:  Biomarkers; Proteomics; Skeletal muscle atrophy; Therapeutic target; Transcriptomics

DOI:  https://doi.org/10.1016/j.jprot.2024.105283
Am J Physiol Endocrinol Metab. 2024 Aug 28.

Enhanced ECCD36 Signaling Promotes Skeletal Muscle Insulin Resistance in Female Mice.

Austin Dada, Javad Habibi, Huma Naz, Dongqing Chen, Guido Lastra, Brian P Bostick, Adam Whaley-Connell, Michael A Hill, James R Sowers, Guanghong Jia.

  Consumption of a Western diet (WD) increases CD36 expression in vascular, hepatic, and skeletal muscle tissues promoting lipid metabolic disorders and insulin resistance. We further examined the role of endothelial cell specific CD36 (ECCD36) signaling in contributing to skeletal muscle lipid metabolic disorders, insulin resistance, and their underlying molecular mechanisms. Female ECCD36 wild type (ECCD36+/+) and knock out (ECCD36-/-) mice, aged six weeks, were provided with either a WD or a standard chow diet for a duration of 16 weeks. ECCD36+/+ WD mice were characterized by elevated fasting plasma glucose and insulin levels, increased homeostatic model assessment for insulin resistance, and glucose intolerance that were blunted in ECCD36-/- mice. Improved insulin sensitivity in ECCD36-/- mice was characterized by increased phosphoinositide 3-kinases/protein kinase B signaling that further augmented glucose transporter type 4 expression and glucose uptake. Meanwhile, 16 weeks of WD feeding also increased skeletal muscle free fatty acid (FFA) and lipid accumulation, without any observed changes in plasma FFA levels. These lipid metabolic disorders were blunted in ECCD36-/- mice. Moreover, ECCD36 also mediated in vitro palmitic acid-induced lipid accumulation in cultured ECs, subsequently leading to the release of FFAs into the culture media. Furthermore, consumption of a WD increased FFA oxidation, mitochondrial dysfunction, impaired mitochondrial respiratory, skeletal muscle fiber type transition, and fibrosis. These WD-induced abnormalities were blunted in ECCD36-/- mice. These findings demonstrate that endothelial specific ECCD36 signaling participates in skeletal muscle FFA uptake, ectopic lipid accumulation, mitochondrial dysfunction, insulin resistance, and associated skeletal muscle dysfunction in diet-induced obesity.

Keywords:  CD36; endothelial cells; insulin resistance; obesity; skeletal muscle

DOI:  https://doi.org/10.1152/ajpendo.00246.2024
Biomedicines. 2024 Jul 24. pii: 1651. [Epub ahead of print]12(8):

Constitutive, Muscle-Specific Orai1 Knockout Results in the Incomplete Assembly of Ca2+ Entry Units and a Reduction in the Age-Dependent Formation of Tubular Aggregates.

Alessia Di Fonso, Matteo Serano, Miao He, Jennifer Leigh, Giorgia Rastelli, Robert T Dirksen, Feliciano Protasi, Laura Pietrangelo.

  Store-operated Ca2+ entry (SOCE) is a ubiquitous cellular mechanism that cells use to activate extracellular Ca2+ entry when intracellular Ca2+ stores are depleted. In skeletal muscle, SOCE occurs within Ca2+ entry units (CEUs), intracellular junctions between stacks of SR membranes containing STIM1 and transverse tubules (TTs) containing ORAI1. Gain-of-function mutations in STIM1 and ORAI1 are linked to tubular aggregate (TA) myopathy, a disease characterized by the atypical accumulation of tubes of SR origin. Moreover, SOCE and TAs are increased in the muscles of aged male mice. Here, we assessed the longitudinal effects (from 4-6 months to 10-14 months of age) of constitutive, muscle-specific Orai1 knockout (cOrai1 KO) on skeletal muscle structure, function, and the assembly of TAs and CEUs. The results from these studies indicate that cOrai1 KO mice exhibit a shorter lifespan, reduced body weight, exercise intolerance, decreased muscle-specific force and rate of force production, and an increased number of structurally damaged mitochondria. In addition, electron microscopy analyses revealed (i) the absence of TAs with increasing age and (ii) an increased number of SR stacks without adjacent TTs (i.e., incomplete CEUs) in cOrai1 KO mice. The absence of TAs is consistent with TAs being formed as a result of excessive ORAI1-dependent Ca2+ entry.

Keywords:  sarcoplasmic reticulum; skeletal muscle; store-operated Ca2+ entry; tubular aggregate myopathy

DOI:  https://doi.org/10.3390/biomedicines12081651
Curr Biol. 2024 Aug 16. pii: S0960-9822(24)01027-3. [Epub ahead of print]

Force-induced dephosphorylation activates the cochaperone BAG3 to coordinate protein homeostasis and membrane traffic.

Judith Ottensmeyer, Alessandra Esch, Henrique Baeta, Sandro Sieger, Yamini Gupta, Maximilian F Rathmann, Andreas Jeschke, Daniel Jacko, Kirill Schaaf, Thorsten Schiffer, Bahareh Rahimi, Lukas Lövenich, Angela Sisto, Peter F M van der Ven, Dieter O Fürst, Albert Haas, Wilhelm Bloch, Sebastian Gehlert, Bernd Hoffmann, Vincent Timmerman, Pitter F Huesgen, Jörg Höhfeld.

  Proteome maintenance in contracting skeletal and cardiac muscles depends on the chaperone-regulating protein BAG3. Reduced BAG3 activity leads to muscle weakness and heart failure in animal models and patients. BAG3 and its chaperone partners recognize mechanically damaged muscle proteins and initiate their disposal through chaperone-assisted selective autophagy (CASA). However, molecular details of the force-dependent regulation of BAG3 have remained elusive so far. Here, we demonstrate that mechanical stress triggers the dephosphorylation of BAG3 in human muscle and in isolated cells. We identify force-regulated phospho-switches in BAG3 that control CASA complex assembly and CASA activity. Differential proteomics reveal RAB GTPases, which organize membrane traffic and fusion, as dephosphorylation-dependent interactors of BAG3. In fact, RAB7A and RAB11B are shown here to be essential for CASA in skeletal muscle cells. Moreover, BAG3 dephosphorylation is also observed upon induction of mitophagy, suggesting an involvement of the cochaperone in the RAB7A-dependent autophagic engulfment of damaged mitochondria in exercised muscle. Cooperation of BAG3 with RAB7A relies on a direct interaction of both proteins, which is regulated by the nucleotide state of the GTPase and by association with the autophagosome membrane protein LC3B. Finally, we provide evidence that BAG3 and RAB7A also cooperate in non-muscle cells and propose that overactivation of CASA in RAB7A-L129F patients contributes to the loss of peripheral neurons in Charcot-Marie-Tooth neuropathy.

Keywords:  autophagy; exercise; membrane trafficking; molecular chaperones; myopathy; neurodegeneration; protein degradation

DOI:  https://doi.org/10.1016/j.cub.2024.07.088
J Nutr Biochem. 2024 Aug 26. pii: S0955-2863(24)00178-5. [Epub ahead of print] 109747

Paternal exercise induces antioxidant defenses by α-Klotho/Keap1 pathways in the skeletal muscle of offspring exposed to a high fat-diet without changing telomere length.

Ivo Vieira de Sousa Neto, Ana Paula Pinto, Rosangela Vieira de Andrade, Fabiane Hiratsuka Veiga de Souza, Paulo Eduardo Narcizo de Souza, Victória Assis, Ramires Alsamir Tibana, Rodrigo Vanerson Passos Neves, Thiago Dos Santos Rosa, Jonato Prestes, Adelino Sanchez Ramos da Silva, Rita de Cassia Marqueti.

  Although previous studies demonstrated that the ancestral lifestyle can enhance the metabolic health of offspring exposed to an obesogenic diet, the specific connections between these positive effects in redox state and telomere length are unknown. We investigated the impact of paternal resistance training (RT) on stress-responsive signaling and the pathways involved in telomere homeostasis in skeletal muscle. This investigation encompassed both the fathers and first-generation litter exposed to a long-term standard diet (24 weeks) and high fat diet (HFD). Wistar rats were randomized into sedentary or trained fathers (8 weeks of resistance training). The offspring were obtained by mating with sedentary females. Upon weaning, male offspring were divided into four groups: offspring of sedentary or trained fathers exposed to either a control diet or HFD. The gastrocnemius was prepared for reverse transcription-quantitative polymerase chain reaction, immunoblotting, ELISA, and electron paramagnetic resonance spectroscopy. RT upregulated shelterin mRNA levels and antioxidant protein, preserving muscle telomere in fathers. Conversely, HFD induced a disturbance in the redox balance, which may have contributed to the offspring telomere shortening from sedentary fathers. Pre-conceptional paternal RT downregulates Kelch-like ECH-associated protein 1 (Keap1) mRNA levels in the skeletal muscle of progeny exposed to HFD, driving an increase in Glutathione reductase mRNA levels, Sod1 and Catalase protein levels to mitigate ROS production. Also, paternal exercise upregulates α-Klotho protein levels, mediating antioxidative responses without altering shelterin mRNA levels and telomere length. We provide the first in-depth analysis that the offspring's redox state seems to be directly associated with the beneficial effects of paternal exercise.

Keywords:  epigenetic landscape; exercise; redox mechanism; unhealthy diet

DOI:  https://doi.org/10.1016/j.jnutbio.2024.109747
Essays Biochem. 2024 Aug 28. pii: EBC20240006. [Epub ahead of print]

Does AMPK bind glycogen in skeletal muscle or is the relationship correlative?

Barnaby P Frankish, Robyn M Murphy.

  Since its discovery over five decades ago, an emphasis on better understanding the structure and functional role of AMPK has been prevalent. In that time, the role of AMPK as a heterotrimeric enzyme that senses the energy state of various cell types has been established. Skeletal muscle is a dynamic, plastic tissue that adapts to both functional and metabolic demands of the human body, such as muscle contraction or exercise. With a deliberate focus on AMPK in skeletal muscle, this review places a physiological lens to the association of AMPK and glycogen that has been established biochemically. It discusses that, to date, no in vivo association of AMPK with glycogen has been shown and this is not altered with interventions, either by physiological or biochemical utilisation of glycogen in skeletal muscle. The reason for this is likely due to the persistent phosphorylation of Thr148 in the β-subunit of AMPK which prevents AMPK from binding to carbohydrate domains. This review presents the correlative data that suggests AMPK senses glycogen utilisation through a direct interaction with glycogen, the biochemical data showing that AMPK can bind carbohydrate in vitro, and highlights that in a physiological setting of rodent skeletal muscle, AMPK does not directly bind to glycogen.

Keywords:  AMPK; glycogen; skeletal muscle

DOI:  https://doi.org/10.1042/EBC20240006
Redox Biol. 2024 Aug 20. pii: S2213-2317(24)00297-0. [Epub ahead of print]76 103319

Mitohormesis during advanced stages of Duchenne muscular dystrophy reveals a redox-sensitive creatine pathway that can be enhanced by the mitochondrial-targeting peptide SBT-20.

Meghan C Hughes, Sofhia V Ramos, Aditya N Brahmbhatt, Patrick C Turnbull, Nazari N Polidovitch, Madison C Garibotti, Uwe Schlattner, Thomas J Hawke, Jeremy A Simpson, Peter H Backx, Christopher Gr Perry.

  Mitochondrial creatine kinase (mtCK) regulates the "fast" export of phosphocreatine to support cytoplasmic phosphorylation of ADP to ATP which is more rapid than direct ATP export. Such "creatine-dependent" phosphate shuttling is attenuated in several muscles, including the heart, of the D2.mdx mouse model of Duchenne muscular dystrophy at only 4 weeks of age. However, the degree to which creatine-dependent and -independent systems of phosphate shuttling progressively worsen or potentially adapt in a hormetic manner throughout disease progression remains unknown. Here, we performed a series of proof-of-principle investigations designed to determine how phosphate shuttling pathways worsen or adapt in later disease stages in D2.mdx (12 months of age). We also determined whether changes in creatine-dependent phosphate shuttling are linked to alterations in mtCK thiol redox state. In permeabilized muscle fibres prepared from cardiac left ventricles, we found that 12-month-old male D2.mdx mice have reduced creatine-dependent pyruvate oxidation and elevated complex I-supported H2O2 emission (mH2O2). Surprisingly, creatine-independent ADP-stimulated respiration was increased and mH2O2 was lowered suggesting that impairments in the faster mtCK-mediated phosphocreatine export system resulted in compensation of the alternative slower pathway of ATP export. The apparent impairments in mtCK-dependent bioenergetics occurred independent of mtCK protein content but were related to greater thiol oxidation of mtCK and a more oxidized cellular environment (lower GSH:GSSG). Next, we performed a proof-of-principle study to determine whether creatine-dependent bioenergetics could be enhanced through chronic administration of the mitochondrial-targeting, ROS-lowering tetrapeptide, SBT-20. We found that 12 weeks of daily treatment with SBT-20 (from day 4-∼12 weeks of age) increased respiration and lowered mH2O2 only in the presence of creatine in D2.mdx mice without affecting calcium-induced mitochondrial permeability transition activity. In summary, creatine-dependent mitochondrial bioenergetics are attenuated in older D2.mdx mice in relation to mtCK thiol oxidation that seem to be countered by increased creatine-independent phosphate shuttling as a unique form of mitohormesis. Separate results demonstrate that creatine-dependent bioenergetics can also be enhanced with a ROS-lowering mitochondrial-targeting peptide. These results demonstrate a specific relationship between redox stress and mitochondrial hormetic reprogramming during dystrophin deficiency with proof-of-principle evidence that creatine-dependent bioenergetics could be modified with mitochondrial-targeting small peptide therapeutics.

Keywords:  Antioxidant; Creatine; Mitochondria; Muscle; Respiration; Small molecule therapy

DOI:  https://doi.org/10.1016/j.redox.2024.103319
Free Radic Biol Med. 2024 Aug 24. pii: S0891-5849(24)00624-5. [Epub ahead of print]

CaMKII protein expression and phosphorylation in human skeletal muscle by immunoblotting: isoform specificity.

Miriam Martinez-Canton, Angel Gallego-Selles, Victor Galvan-Alvarez, Eduardo Garcia-Gonzalez, Giovanni Garcia-Perez, Alfredo Santana, Marcos Martin-Rincon, Jose A L Calbet.

  Calcium (Ca2+)/calmodulin-dependent protein kinase II (CaMKII) is activated during exercise by reactive oxygen species (ROS) and Ca2+ transients initiating muscle contraction. CaMKII modulates the antioxidant, inflammatory, metabolic and autophagy signalling pathways. CaMKII is coded by four homologous genes (α, β, γ, and δ). In rat skeletal muscle δD, δA, γD, γB and βM have been described while different characterisations of human skeletal muscle CaMKII isoforms have been documented. Precisely discerning between the various isoforms is pivotal for understanding their distinctive functions and regulatory mechanisms in response to exercise and other stimuli. This study aimed to optimise the detection of the different CaMKII isoforms by western blotting using eight different CaMKII commercial antibodies in human skeletal muscle. This research describes a systematic and cost-effective approach to discern between CaMKII isoforms in human skeletal muscle. Exercise-induced posttranslational modifications, i.e. phosphorylation and oxidations, allowed the identification of specific bands by multitargeting them with different antibodies after stripping and reprobing. The methodology proposed has confirmed the molecular weight of βM CaMKII and allows distinguishing between γ/δ and δD CaMKII. The corresponding molecular weight for the CaMKII isoforms resolved were: δD, at 54.2±2.1kDa; γ/δ, at 59±1.2kDa and 61.6±1.3kDa; and βM isoform, at 76±1.8kDa. Some tested antibodies showed high specificity for the δD isoform, the most responsive to ROS and intracellular Ca2+ transients isoform in human skeletal muscle, while others, despite the commercial claims, failed to show such specificity.

Keywords:  Calcium/calmodulin-dependent protein kinase II isoforms; exercise; human; immunoblotting; signalling; skeletal muscle

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.08.030
Mol Metab. 2024 Aug 27. pii: S2212-8778(24)00146-7. [Epub ahead of print] 102015

Loss of mitochondria long-chain fatty acid oxidation impairs skeletal muscle contractility by disrupting myofibril structure and calcium homeostasis.

Andrea S Pereyra, Regina F Fernandez, Adam Amorese, Jasmine N Castro, Chien-Te Lin, Espen E Spangenburg, Jessica M Ellis.

  Abnormal lipid metabolism in mammalian tissues can be highly deleterious, leading to organ failure. Carnitine Palmitoyltransferase 2 (CPT2) deficiency is an inherited metabolic disorder affecting the liver, heart, and skeletal muscle due to impaired mitochondrial oxidation of long-chain fatty acids (mLCFAO) for energy production. However, the basis of tissue damage in mLCFAO disorders is not fully understood. Mice lacking CPT2 in skeletal muscle (Cpt2Sk-/-) were generated to investigate the nexus between mFAO deficiency and myopathy. Compared to controls, ex-vivo contractile force was reduced by 70% in Cpt2Sk-/- oxidative soleus muscle despite the preserved capacity to couple ATP synthesis to mitochondrial respiration on alternative substrates to long-chain fatty acids. Increased mitochondrial biogenesis, lipid accumulation, and the downregulation of 80% of dystrophin-related and contraction-related proteins severely compromised the structure and function of Cpt2Sk-/- soleus. CPT2 deficiency affected oxidative muscles more than glycolytic ones. Exposing isolated sarcoplasmic reticulum to long-chain acylcarnitines (LCACs) inhibited calcium uptake. In agreement, Cpt2Sk-/- soleus had decreased calcium uptake and significant accumulation of palmitoyl-carnitine, suggesting that LCACs and calcium dyshomeostasis are linked in skeletal muscle. Our data demonstrate that loss of CPT2 and mLCFAO compromise muscle structure and function due to excessive mitochondrial biogenesis, downregulation of the contractile proteome, and disruption of calcium homeostasis.

Keywords:  CPT2; Calcium; Fatty acid oxidation; Muscle contraction; Palmitoyl-carnitine

DOI:  https://doi.org/10.1016/j.molmet.2024.102015
Protein Sci. 2024 Sep;33(9): e5156

An atlas of caspase cleavage events in differentiating muscle cells.

Erik Gomez-Cardona, Mahshid H Dehkordi, Kolden Van Baar, Aiste Vitkauskaite, Olivier Julien, Howard O Fearnhead.

  Executioner caspases, such as caspase-3, are known to induce apoptosis, but in other contexts, they can control very different fates, including cell differentiation and neuronal plasticity. While hundreds of caspase substrates are known to be specifically targeted during cell death, we know very little about how caspase activity brings about non-apoptotic fates. Here, we report the first proteome identification of cleavage events in C2C12 cells undergoing myogenic differentiation and its comparison to undifferentiated or dying C2C12 cells. These data have identified new caspase substrates, including caspase substrates specifically associated with differentiation, and show that caspases are regulating proteins involved in myogenesis in myotubes, several days after caspase-3 initiated differentiation. Cytoskeletal proteins emerged as a major group of non-apoptotic caspase substrates. We also identified proteins with well-established roles in muscle differentiation as substrates cleaved in differentiating cells.

Keywords:  C2C12; apoptosis; caspase; differentiation

DOI:  https://doi.org/10.1002/pro.5156
Nat Commun. 2024 Aug 28. 15(1): 7440

CaV1.1 voltage-sensing domain III exclusively controls skeletal muscle excitation-contraction coupling.

Simone Pelizzari, Martin C Heiss, Monica L Fernández-Quintero, Yousra El Ghaleb, Klaus R Liedl, Petronel Tuluc, Marta Campiglio, Bernhard E Flucher.

Skeletal muscle contractions are initiated by action potentials, which are sensed by the voltage-gated calcium channel (CaV1.1) and are conformationally coupled to calcium release from intracellular stores. Notably, CaV1.1 contains four separate voltage-sensing domains (VSDs), which activate channel gating and excitation-contraction (EC-) coupling at different voltages and with distinct kinetics. Here we show that a single VSD of CaV1.1 controls skeletal muscle EC-coupling. Whereas mutations in VSDs I, II and IV affect the current properties but not EC-coupling, only mutations in VSD III alter the voltage-dependence of depolarization-induced calcium release. Molecular dynamics simulations reveal comprehensive, non-canonical state transitions of VSD III in response to membrane depolarization. Identifying the voltage sensor that activates EC-coupling and detecting its unique conformational changes opens the door to unraveling the downstream events linking VSD III motion to the opening of the calcium release channel, and thus resolving the signal transduction mechanism of skeletal muscle EC-coupling.

DOI: https://doi.org/10.1038/s41467-024-51809-5
Ann Neurol. 2024 Aug 27.

Single-Nucleus RNA Sequencing Unravels Early Mechanisms of Human Becker Muscular Dystrophy.

Zhihao Xie, Chang Liu, Chengyue Sun, Yilin Liu, Jieru Peng, Lingchao Meng, Jianwen Deng, Zhaoxia Wang, Chunxia Yang, Yun Yuan, Zhiying Xie.

OBJECTIVE: The transcriptional heterogeneity at a single-nucleus level in human Becker muscular dystrophy (BMD) dystrophic muscle has not been explored. Here, we aimed to understand the transcriptional heterogeneity associated with myonuclei, as well as other mononucleated cell types that underly BMD pathogenesis by performing single-nucleus RNA sequencing.
METHODS: We profiled single-nucleus transcriptional profiles of skeletal muscle samples from 7 BMD patients and 3 normal controls.
RESULTS: A total of 17,216 nuclei (12,879 from BMD patients and 4,337 from controls) were classified into 13 known cell types, including 9 myogenic lineages and 4 non-myogenic lineages, and 1 unclassified nuclear type according to their cell identities. Among them, type IIx myonuclei were the first to degenerate in response to dystrophin reduction. Differential expression analysis revealed that the fibro-adipogenic progenitors (FAPs) population had the largest transcriptional changes among all cell types. Sub-clustering analysis identified a significantly compositional increase in the activated FAPs (aFAPs) subpopulation in BMD muscles. Pseudotime analysis, regulon inference, and deconvolution analysis of bulk RNA-sequencing data derived from 29 BMD patients revealed that the aFAPs subpopulation, a distinctive and previously unrecognized mononuclear subtype, was profibrogenic and expanded in BMD patients. Muscle quantitative real-time polymerase chain reaction and immunofluorescence analysis confirmed that the mRNA and protein levels of the aFAPs markers including LUM, DCN, and COL1A1 in BMD patients were significantly higher than those in controls, respectively.
INTERPRETATION: Our results provide insights into the transcriptional diversity of human BMD muscle at a single-nucleus resolution and new potential targets for anti-fibrosis therapies in BMD. ANN NEUROL 2024.

DOI: https://doi.org/10.1002/ana.27070
Elife. 2024 Aug 28. pii: RP95229. [Epub ahead of print]13

Senescent cells inhibit mouse myoblast differentiation via the SASP-lipid 15d-PGJ2 mediated modification and control of HRas.

Swarang Sachin Pundlik, Alok Barik, Ashwin Venkateshvaran, Snehasudha Subhadarshini Sahoo, Mahapatra Anshuman Jaysingh, Raviswamy G H Math, Heera Lal, Maroof Athar Hashmi, Arvind Ramanathan.

  Senescent cells are characterized by multiple features such as increased expression of senescence-associated β-galactosidase activity (SA β-gal) and cell cycle inhibitors such as p21 or p16. They accumulate with tissue damage and dysregulate tissue homeostasis. In the context of skeletal muscle, it is known that agents used for chemotherapy such as Doxorubicin (Doxo) cause buildup of senescent cells, leading to the inhibition of tissue regeneration. Senescent cells influence the neighboring cells via numerous secreted factors which form the senescence-associated secreted phenotype (SASP). Lipids are emerging as a key component of SASP that can control tissue homeostasis. Arachidonic acid-derived lipids have been shown to accumulate within senescent cells, specifically 15d-PGJ2, which is an electrophilic lipid produced by the non-enzymatic dehydration of the prostaglandin PGD2. This study shows that 15d-PGJ2 is also released by Doxo-induced senescent cells as an SASP factor. Treatment of skeletal muscle myoblasts with the conditioned medium from these senescent cells inhibits myoblast fusion during differentiation. Inhibition of L-PTGDS, the enzyme that synthesizes PGD2, diminishes the release of 15d-PGJ2 by senescent cells and restores muscle differentiation. We further show that this lipid post-translationally modifies Cys184 of HRas in C2C12 mouse skeletal myoblasts, causing a reduction in the localization of HRas to the Golgi, increased HRas binding to Ras Binding Domain (RBD) of RAF Kinase (RAF-RBD), and activation of cellular Mitogen Activated Protein (MAP) kinase-Extracellular Signal Regulated Kinase (Erk) signaling (but not the Akt signaling). Mutating C184 of HRas prevents the ability of 15d-PGJ2 to inhibit the differentiation of muscle cells and control the activity of HRas. This work shows that 15d-PGJ2 released from senescent cells could be targeted to restore muscle homeostasis after chemotherapy.

Keywords:  HRas; SASP; biochemistry; chemical biology; mouse; muscle differentiation; oxylipins; senescence

DOI:  https://doi.org/10.7554/eLife.95229
Physiol Meas. 2024 Aug 23.

Progression of total training volume in resistance training studies and its application to skeletal muscle growth.

William B Hammert, Ryo Kataoka, Yujiro Yamada, Jun Seob Song, Anna Kang, Robert W Spitz, Jeremy P Loenneke.

  Progressive overload describes the gradual increase of stress placed on the body during exercise training, and is often quantified (i.e., in resistance training studies) through increases in total training volume (i.e., sets x repetitions x load) from the first to final week of the exercise training intervention. Within the literature, it has become increasingly common for authors to discuss skeletal muscle growth adaptations in the context of increases in total training volume (i.e., the magnitude progression in total training volume). The present manuscript discusses a physiological rationale for progressive overload and then explains why, in our opinion, quantifying the progression of total training volume within research investigations tells very little about muscle growth adaptations to resistance training. Our opinion is based on the following research findings: (1) a noncausal connection between increases in total training volume (i.e., progressively overloading the resistance exercise stimulus) and increases in skeletal muscle size; (2) similar changes in total training volume may not always produce similar increases in muscle size; and (3) the ability to exercise more and consequently amass larger increases in total training volume may not inherently produce more skeletal muscle growth. The methodology of quantifying changes in total training volume may therefore provide a means through which researchers can mathematically determine the total amount of external "work" performed within a resistance training study. It may not, however, always explain muscle growth adaptations. &#xD.

Keywords:  muscle growth; progressive overload; resistance training volume

DOI:  https://doi.org/10.1088/1361-6579/ad7348
Clin Pract. 2024 Jul 25. 14(4): 1451-1467

Dietary Protein and Physical Exercise for the Treatment of Sarcopenia.

Rosarita Nasso, Antonio D'Errico, Maria Letizia Motti, Mariorosario Masullo, Rosaria Arcone.

  Sarcopenia is a multifactorial age-related disorder that causes a decrease in muscle mass, strength, and function, leading to alteration of movement, risk of falls, and hospitalization. This article aims to review recent findings on the factors underlying sarcopenia and the strategies required to delay and counteract its symptoms. We focus on molecular factors linked to ageing, on the role of low-grade chronic and acute inflammatory conditions such as cancer, which contributes to the onset of sarcopenia, and on the clinical criteria for its diagnosis. The use of drugs against sarcopenia is still subject to debate, and the suggested approaches to restore muscle health are based on adequate dietary protein intake and physical exercise. We also highlight the difference in the amount and quality of amino acids within animal- and plant-based diets, as studies have often shown varying results regarding their effect on sarcopenia in elderly people. In addition, many studies have reported that non-pharmacological approaches, such as an optimization of dietary protein intake and training programs based on resistance exercise, can be effective in preventing and delaying sarcopenia. These approaches not only improve the maintenance of skeletal muscle function, but also reduce health care costs and improve life expectancy and quality in elderly people.

Keywords:  ageing; dietary proteins; myokines; physical exercise; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.3390/clinpract14040117
Curr Opin Endocr Metab Res. 2024 Jun;35 100525

Metabolic small talk during exercise: The role of metabokines and lipokines in interorgan signalling.

Shaimaa A Gad, Hannah Smith, Lee D Roberts.

  Metabolites in exercise have traditionally been viewed as a fuel source, waste product, or anabolic components required for exercise-induced biosynthetic processes. However, it is now recognised that metabolites and lipids may act as mediators of interorgan crosstalk to coordinate the local and systemic physiological adaptations required to meet the complex system-wide challenge of exercise. These bioactive metabolite and lipid signals have been termed metabokines and lipokines, respectively. There is emerging evidence that metabokines and lipokines contribute to the health benefits of exercise. This review highlights several of the key recent discoveries related to metabokine and lipokine signalling during exercise. The discovery of these metabokines and lipokines, and their signalling targets, may provide the basis of future therapies for human disease.

Keywords:  Exercise; Interorgan signalling; Lipokine; Metabokine; Metabolism; Metabolite; Skeletal muscle

DOI:  https://doi.org/10.1016/j.coemr.2024.100525
J Cachexia Sarcopenia Muscle. 2024 Aug 27.

Hydrogen sulfide inhibits skeletal muscle ageing by up-regulating autophagy through promoting deubiquitination of adenosine 5'-monophosphate (AMP)-activated protein kinase α1 via ubiquitin specific peptidase 5.

Jia-He Yang, Jun Gao, Ya-Qi E, Li-Jie Jiao, Ren Wu, Qiu-Yi Yan, Zi-Yi Wei, Guo-Liang Yan, Jin-Long Liang, Hong-Zhu Li.

   BACKGROUND: Hydrogen sulfide (H2S), the third gasotransmitter discovered, regulates a variety of physiological functions. Whether H2S alleviates skeletal muscle ageing by regulating autophagy has not been reported.
METHODS: Mice were administered 150 mg/kg/day of D-galactose ( D-gal), and C2C12 myotubes were cultured in 20 g/L D-gal to induce ageing. Sodium hydrosulfide (NaHS) was employed as an exogenous donor in the treatment group. The intracellular concentration of H2S was quantified by the 7-azido-4-methylcoumarin fluorescence probe. The proteins involved in the ubiquitin-mediated degradation of AMPKα1 were detected by liquid chromatography tandem mass spectrometry (LC-MS/MS) and co-immunoprecipitation (Co-IP). S-sulfhydration of USP5 was tested by a biotin-switch assay. Associated proteins were analysed by western blot.
RESULTS: NaHS was found to effectively restore the H2S content in both ageing gastrocnemius (+91.89%, P < 0.001) and C2C12 myotubes (+27.55%, P < 0.001). In comparison to the D-gal group, NaHS was observed to increase the mean cross-sectional area of muscle fibres (+44.91%, P < 0.001), to decrease the collagen volume fraction of gastrocnemius (-81.32%, P = 0.001) and to reduce the β-galactosidase-positive area of C2C12 myotubes (-28.74%, P < 0.001). NaHS was also found to reverse the expression of muscle atrophy F box protein (MAFbx), muscle-specific RING finger protein 1 (MuRF1), Cyclin D1 and p21 in the ageing gastrocnemius tissue (MAFbx: -31.73%, P = 0.008; MuRF1: -32.37%, P = 0.003; Cyclin D1: +45.34%, P = 0.010; p21: -25.53%, P = 0.022) and C2C12 myotubes (MAFbx: -16.38%, P < 0.001; MuRF1: -16.45%, P = 0.003; Cyclin D1: +40.23%, P < 0.001; p21: -35.85%, P = 0.026). The AMPKα1-ULK1 pathway was activated and autophagy was up-regulated in NaHS-treated gastrocnemius tissue (p-AMPKα1: +61.61%, P = 0.018; AMPKα1: +30.64%, P = 0.010; p-ULK1/ULK1: +85.87%, P = 0.005; p62: -29.07%, P < 0.001; Beclin1: +24.75%, P = 0.007; light chain 3 II/I [LC3 II/I]: +55.78%, P = 0.004) and C2C12 myotubes (p-AMPKα1: +77.49%, P = 0.018; AMPKα1: +26.18%, P = 0.022; p-ULK1/ULK1: +38.34%, P = 0.012; p62: -9.02%, P = 0.014; Beclin1: +13.36%, P < 0.001; LC3 II/I: +79.38%, P = 0.017; autophagy flux: +24.88%, P = 0.034) compared with the D-gal group. The effects of NaHS on autophagy were comparable to those of acadesine and LYN-1604, and chloroquine could reverse its effects on ageing. LC-MS/MS and Co-IP experiments demonstrated that USP5 is a deubiquitinating enzyme of AMPKα1. Following the knockdown of USP5, the activation of AMPKα1 was decreased (p-AMPKα1: -42.10%, P < 0.001; AMPKα1: -43.93%, P < 0.001), autophagy was inhibited (p-ULK1/ULK1: -27.51, P = 0.001; p62: +36.00, P < 0.001; Beclin1: -22.15%, P < 0.001) and NaHS lost its ability to up-regulate autophagy. NaHS was observed to restore the expression (gastrocnemius: +62.17%, P < 0.001; C2C12 myotubes: +37.51%, P = 0.003) and S-sulfhydration (+53.07%, P = 0.009) of USP5 and reduce the ubiquitination of AMPKα1.
CONCLUSIONS: H2S promotes the deubiquitination of AMPKα1 by increasing the expression and S-sulfhydration of USP5, thereby up-regulating autophagy and alleviating skeletal muscle ageing.

Keywords:  ageing; autophagy; deubiquitination; hydrogen sulfide; skeletal muscle

DOI:  https://doi.org/10.1002/jcsm.13560
Int J Mol Sci. 2024 Aug 12. pii: 8771. [Epub ahead of print]25(16):

Caveolin and NOS in the Development of Muscular Dystrophy.

Moeka Nakashima, Naoko Suga, Sayuri Yoshikawa, Satoru Matsuda.

  Caveolin is a structural protein within caveolae that may be involved in transmembrane molecular transport and/or various intercellular interactions within cells. Specific mutations of caveolin-3 in muscle fibers are well known to cause limb-girdle muscular dystrophy. Altered expression of caveolin-3 has also been detected in Duchenne muscular dystrophy, which may be a part of the pathological process leading to muscle weakness. Interestingly, it has been shown that the renovation of nitric oxide synthase (NOS) in sarcolemma with muscular dystrophy could improve muscle health, suggesting that NOS may be involved in the pathology of muscular dystrophy. Here, we summarize the notable function of caveolin and/or NOS in skeletal muscle fibers and discuss their involvement in the pathology as well as possible tactics for the innovative treatment of muscular dystrophies.

Keywords:  Duchenne muscular dystrophy; NOS; caveolae; caveolin; gut microbiota; limb–girdle muscular dystrophy; probiotics

DOI:  https://doi.org/10.3390/ijms25168771
Int J Mol Sci. 2024 Aug 16. pii: 8909. [Epub ahead of print]25(16):

Chikungunya and Mayaro Viruses Induce Chronic Skeletal Muscle Atrophy Triggered by Pro-Inflammatory and Oxidative Response.

Mariana Oliveira Lopes da Silva, Camila Menezes Figueiredo, Rômulo Leão Silva Neris, Iris Paula Guimarães-Andrade, Daniel Gavino-Leopoldino, Leonardo Linhares Miler-da-Silva, Helber da Maia Valença, Leandro Ladislau, Caroline Victorino Felix de Lima, Fernanda Meireles Coccarelli, Claudia Farias Benjamim, Iranaia Assunção-Miranda.

  Chikungunya (CHIKV) and Mayaro (MAYV) viruses are arthritogenic alphaviruses that promote an incapacitating and long-lasting inflammatory muscle-articular disease. Despite studies pointing out the importance of skeletal muscle (SkM) in viral pathogenesis, the long-term consequences on its physiology and the mechanism of persistence of symptoms are still poorly understood. Combining molecular, morphological, nuclear magnetic resonance imaging, and histological analysis, we conduct a temporal investigation of CHIKV and MAYV replication in a wild-type mice model, focusing on the impact on SkM composition, structure, and repair in the acute and late phases of infection. We found that viral replication and induced inflammation promote a rapid loss of muscle mass and reduction in fiber cross-sectional area by upregulation of muscle-specific E3 ubiquitin ligases MuRF1 and Atrogin-1 expression, both key regulators of SkM fibers atrophy. Despite a reduction in inflammation and clearance of infectious viral particles, SkM atrophy persists until 30 days post-infection. The genomic CHIKV and MAYV RNAs were still detected in SkM in the late phase, along with the upregulation of chemokines and anti-inflammatory cytokine expression. In agreement with the involvement of inflammatory mediators on induced atrophy, the neutralization of TNF and a reduction in oxidative stress using monomethyl fumarate, an agonist of Nrf2, decreases atrogen expression and atrophic fibers while increasing weight gain in treated mice. These data indicate that arthritogenic alphavirus infection could chronically impact body SkM composition and also harm repair machinery, contributing to a better understanding of mechanisms of arthritogenic alphavirus pathogenesis and with a description of potentially new targets of therapeutic intervention.

Keywords:  arthritogenic alphavirus; chronic atrophy; inflammation; oxidative stress; skeletal muscle

DOI:  https://doi.org/10.3390/ijms25168909
Int J Mol Sci. 2024 Aug 06. pii: 8577. [Epub ahead of print]25(16):

Increased Homer Activity and NMJ Localization in the Vestibular Lesion het-/- Mouse soleus Muscle.

Gabor Trautmann, Katharina Block, Martina Gutsmann, Stéphane Besnard, Sandra Furlan, Pierre Denise, Pompeo Volpe, Dieter Blottner, Michele Salanova.

  We investigated the shuttling of Homer protein isoforms identified in soluble (cytosolic) vs. insoluble (membrane-cytoskeletal) fraction and Homer protein-protein interaction/activation in the deep postural calf soleus (SOL) and non-postural gastrocnemius (GAS) muscles of het-/- mice, i.e., mice with an autosomal recessive variant responsible for a vestibular disorder, in order to further elucidate a) the underlying mechanisms of disrupted vestibular system-derived modulation on skeletal muscle, and b) molecular signaling at respective neuromuscular synapses. Heterozygote mice muscles served as the control (CTR). An increase in Homer cross-linking capacity was present in the SOL muscle of het-/- mice as a compensatory mechanism for the altered vestibule system function. Indeed, in both fractions, different Homer immunoreactive bands were detectable, as were Homer monomers (~43-48 kDa), Homer dimers (~100 kDa), and several other Homer multimer bands (>150 kDA). The het-/- GAS particulate fraction showed no Homer dimers vs. SOL. The het-/- SOL soluble fraction showed a twofold increase (+117%, p ≤ 0.0004) in Homer dimers and multimers. Homer monomers were completely absent from the SOL independent of the animals studied, suggesting muscle-specific changes in Homer monomer vs. dimer expression in the postural SOL vs. the non-postural GAS muscles. A morphological assessment showed an increase (+14%, p ≤ 0.0001) in slow/type-I myofiber cross-sectional area in the SOL of het-/- vs. CTR mice. Homer subcellular immuno-localization at the neuromuscular junction (NMJ) showed an altered expression in the SOL of het-/-mice, whereas only not-significant changes were found for all Homer isoforms, as judged by RT-qPCR analysis. Thus, muscle-specific changes, myofiber properties, and neuromuscular signaling mechanisms share causal relationships, as highlighted by the variable subcellular Homer isoform expression at the instable NMJs of vestibular lesioned het-/- mice.

Keywords:  Homer; NMJ; vestibular lesion

DOI:  https://doi.org/10.3390/ijms25168577
Int J Mol Sci. 2024 Aug 13. pii: 8800. [Epub ahead of print]25(16):

Ubiquitination Insight from Spinal Muscular Atrophy-From Pathogenesis to Therapy: A Muscle Perspective.

Alfonso Bolado-Carrancio, Olga Tapia, José C Rodríguez-Rey.

  Spinal muscular atrophy (SMA) is one of the most frequent causes of death in childhood. The disease's molecular basis is deletion or mutations in the SMN1 gene, which produces reduced survival motor neuron protein (SMN) levels. As a result, there is spinal motor neuron degeneration and a large increase in muscle atrophy, in which the ubiquitin-proteasome system (UPS) plays a significant role. In humans, a paralogue of SMN1, SMN2 encodes the truncated protein SMNΔ7. Structural differences between SMN and SMNΔ7 affect the interaction of the proteins with UPS and decrease the stability of the truncated protein. SMN loss affects the general ubiquitination process by lowering the levels of UBA1, one of the main enzymes in the ubiquitination process. We discuss how SMN loss affects both SMN stability and the general ubiquitination process, and how the proteins involved in ubiquitination could be used as future targets for SMA treatment.

Keywords:  SMN; skeletal muscle atrophy; spinal muscular atrophy; ubiquitin–proteasome system

DOI:  https://doi.org/10.3390/ijms25168800
J Clin Invest. 2024 Aug 27. pii: e173858. [Epub ahead of print]

Spatiotemporal transcriptomic mapping of regenerative inflammation in skeletal muscle reveals a dynamic multilayered tissue architecture.

Andreas Patsalos, Laszlo Halasz, Darby Oleksak, Xiaoyan Wei, Gergely Nagy, Petros Tzerpos, Thomas Conrad, David W Hammers, H Lee Sweeney, Laszlo Nagy.

  Tissue regeneration is orchestrated by macrophages that clear damaged cells and promote regenerative inflammation. How macrophages spatially adapt and diversify their functions to support the architectural requirements of actively regenerating tissue remains unknown. In this study, we reconstructed the dynamic trajectories of myeloid cells isolated from acutely injured and early-stage dystrophic muscles. We identified divergent subsets of monocytes/macrophages and dendritic cells (DCs) and validated markers (e.g., GPNMB) and transcriptional regulators associated with defined functional states. In dystrophic muscle, specialized repair-associated subsets exhibited distinct macrophage diversity and reduced DC heterogeneity. Integrating spatial transcriptomics analyses with immunofluorescence uncovered the ordered distribution of subpopulations and multilayered regenerative inflammation zones (RIZs) where distinct macrophage subsets are organized in functional zones around damaged myofibers supporting all phases of regeneration. Importantly, intermittent glucocorticoid treatment disrupted the RIZs. Our findings suggest that macrophage subtypes mediated the development of the highly ordered architecture of regenerative tissues, unveiling the principles of the structured yet dynamic nature of regenerative inflammation supporting effective tissue repair.

Keywords:  Expression profiling; Inflammation; Macrophages; Skeletal muscle

DOI:  https://doi.org/10.1172/JCI173858
Bone Joint Res. 2024 Aug 28. 13(8): 411-426

Identification of the molecular link: STAT3 is a shared key gene linking postmenopausal osteoporosis and sarcopenia.

Dian Liu, Ke Wang, Jinpeng Wang, Fangming Cao, Lin Tao.

Aims: This study explored the shared genetic traits and molecular interactions between postmenopausal osteoporosis (POMP) and sarcopenia, both of which substantially degrade elderly health and quality of life. We hypothesized that these motor system diseases overlap in pathophysiology and regulatory mechanisms.
Methods: We analyzed microarray data from the Gene Expression Omnibus (GEO) database using weighted gene co-expression network analysis (WGCNA), machine learning, and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis to identify common genetic factors between POMP and sarcopenia. Further validation was done via differential gene expression in a new cohort. Single-cell analysis identified high expression cell subsets, with mononuclear macrophages in osteoporosis and muscle stem cells in sarcopenia, among others. A competitive endogenous RNA network suggested regulatory elements for these genes.
Results: Signal transducer and activator of transcription 3 (STAT3) was notably expressed in both conditions. Single-cell analysis pinpointed specific cells with high STAT3 expression, and microRNA (miRNA)-125a-5p emerged as a potential regulator. Experiments confirmed the crucial role of STAT3 in osteoclast differentiation and muscle proliferation.
Conclusion: STAT3 has emerged as a key gene in both POMP and sarcopenia. This insight positions STAT3 as a potential common therapeutic target, possibly improving management strategies for these age-related diseases.

DOI: https://doi.org/10.1302/2046-3758.138.BJR-2023-0351.R2
J Cachexia Sarcopenia Muscle. 2024 Aug 26.

Betaine delays age-related muscle loss by mitigating Mss51-induced impairment in mitochondrial respiration via Yin Yang1.

Si Chen, Tongtong He, Jiedong Chen, Dongsheng Wen, Chen Wang, Wenge Huang, Zhijun Yang, Mengtao Yang, Mengchu Li, Siyu Huang, Zihui Huang, Huilian Zhu.

   BACKGROUND: Mitochondrial dysfunction is one of the hallmarks of aging and a leading contributor to sarcopenia. Nutrients are essential for improving mitochondrial function and skeletal muscle health during the aging process. Betaine is a nutrient with potential muscle-preserving properties. However, whether and how betaine could regulate the mitochondria function in aging muscle are poorly understood. We aimed to explore the molecular target and underlying mechanism of betaine in attenuating the age-related mitochondrial dysfunction in skeletal muscle.
METHODS: Young mice (YOU, 2 months), old mice (OLD, 15 months), and old mice with betaine treatment (BET, 15 months) were fed for 12 weeks. The effects of betaine on muscle mass, strength, function, and subcellular structure of muscle fibres were assessed. RNA sequencing (RNA-seq) was conducted to identify the molecular target of betaine. The impacts of betaine on mitochondrial-related molecules, superoxide accumulation, and oxidative respiration were examined using western blotting (WB), immunofluorescence (IF) and seahorse assay. The underlying mechanism of betaine regulation on the molecular target to maintain mitochondrial function was investigated by luciferase reporter assay, chromatin immunoprecipitation and electrophoretic mobility shift assay. Adenoassociated virus transfection, succinate dehydrogenase staining (SDH), and energy expenditure assessment were performed on 20-month-old mice for validating the mechanism in vivo.
RESULTS: Betaine intervention demonstrated anti-aging effects on the muscle mass (P = 0.017), strength (P = 0.010), and running distance (P = 0.013). Mitochondrial-related markers (ATP5a, Sdha, and Uqcrc2) were 1.1- to 1.5-fold higher in BET than OLD (all P ≤ 0.036) with less wasted mitochondrial vacuoles accumulating in sarcomere. Bioinformatic analysis from RNA-seq displayed pathways related to mitochondrial respiration activity was higher enriched in BET group (NES = -0.87, FDR = 0.10). The quantitative real time PCR (qRT-PCR) revealed betaine significantly reduced the expression of a novel mitochondrial regulator, Mss51 (-24.9%, P = 0.002). In C2C12 cells, betaine restored the Mss51-mediated suppression in mitochondrial respiration proteins (all P ≤ 0.041), attenuated oxygen consumption impairment, and superoxide accumulation (by 20.7%, P = 0.001). Mechanically, betaine attenuated aging-induced repression in Yy1 mRNA expression (BET vs. OLD: 2.06 vs. 1.02, P = 0.009). Yy1 transcriptionally suppressed Mss51 mRNA expression both in vitro and in vivo. This contributed to the preservation of mitochondrial respiration, improvement for energy expenditure (P = 0.008), and delay of muscle loss during aging process.
CONCLUSIONS: Altogether, betaine transcriptionally represses Mss51 via Yy1, improving age-related mitochondrial respiration in skeletal muscle. These findings suggest betaine holds promise as a dietary supplement to delay skeletal muscle degeneration and improve age-related mitochondrial diseases.

Keywords:  Betaine; Mitochondrial dysfunction; Mss51; Muscle loss; Transcription factor; Yin yang1 (Yy1)

DOI:  https://doi.org/10.1002/jcsm.13558
J Therm Biol. 2024 Aug 22. pii: S0306-4565(24)00176-1. [Epub ahead of print]124 103958

N-acetylcysteine stimulates the proliferation and differentiation in heat-stressed skeletal muscle cells.

Jiawei Lu, Peng Zhao, Xiuhu Ding, Huixia Li.

  N-acetylcysteine (NAC) is known for its beneficial effects on health due to its antioxidant and antiapoptotic properties. This study explored the protective effects of NAC against oxidative stress in heat-stressed (HS) skeletal muscle cells and its role in promoting muscle development. NAC reduced the heat shock response by decreasing the expression of heat shock protein 70 (HSP70) in HS-induced muscle cells during proliferation and differentiation. NAC also mitigated HS-induced oxidative stress via increasing the antioxidant enzyme levels and reducing oxidant enzyme levels. Treatment with NAC at 2 mM increased cell viability from 43.68% ± 5.14%-66.69% ± 14.43% and decreased the apoptosis rate from 7.89% ± 0.53%-5.17% ± 0.11% in skeletal muscle cells. Additionally, NAC promoted the proliferation and differentiation of HS-induced skeletal muscle cells by upregulating the expression of PAX7, MYF5, MRF4 and MYHC. These findings suggest that NAC alleviates HS-induced oxidative damage in skeletal muscle cells and support muscle development.

Keywords:  Heat stress; Muscle development; N-Acetylcysteine; Oxidative stress; Skeletal muscle cells

DOI:  https://doi.org/10.1016/j.jtherbio.2024.103958
Exerc Sport Sci Rev. 2024 Aug 01.

Hormones, Hypertrophy, and Hype: An Evidence-guided Primer on Endogenous Endocrine Influences on Exercise-Induced Muscle Hypertrophy.

Derrick W Van Every, Alysha C D'Souza, Stuart M Phillips.

ABSTRACT: We review the evidence indicating that endogenous changes in these hormones, including testosterone, growth hormone, insulin growth factor-1, and estrogen, and their proposed anabolic effects contribute to and augment resistance exercise training (RET)-induced hypertrophy. Additionally, we provide recommendations for gold-standard methodological rigor to establish best practices for verifying menstrual phases as part of their research, ultimately enhancing our understanding of the impact of ovarian hormones on RET-induced adaptations.

DOI: https://doi.org/10.1249/JES.0000000000000346
Elife. 2024 Aug 27. pii: RP96535. [Epub ahead of print]13

Serum proteomic profiling of physical activity reveals CD300LG as a novel exerkine with a potential causal link to glucose homeostasis.

Sindre Lee-Ødegård, Marit Hjorth, Thomas Olsen, Gunn-Helen Moen, Emily Daubney, David M Evans, Andrea L Hevener, Aldons J Lusis, Mingqi Zhou, Marcus M Seldin, Hooman Allayee, James Hilser, Jonas Krag Viken, Hanne Gulseth, Frode Norheim, Christian A Drevon, Kåre Inge Birkeland.

   Background: Physical activity has been associated with preventing the development of type 2 diabetes and atherosclerotic cardiovascular disease. However, our understanding of the precise molecular mechanisms underlying these effects remains incomplete and good biomarkers to objectively assess physical activity are lacking.
Methods: We analyzed 3072 serum proteins in 26 men, normal weight or overweight, undergoing 12 weeks of a combined strength and endurance exercise intervention. We estimated insulin sensitivity with hyperinsulinemic euglycemic clamp, maximum oxygen uptake, muscle strength, and used MRI/MRS to evaluate body composition and organ fat depots. Muscle and subcutaneous adipose tissue biopsies were used for mRNA sequencing. Additional association analyses were performed in samples from up to 47,747 individuals in the UK Biobank, as well as using two-sample Mendelian randomization and mice models.
Results: Following 12 weeks of exercise intervention, we observed significant changes in 283 serum proteins. Notably, 66 of these proteins were elevated in overweight men and positively associated with liver fat before the exercise regimen, but were normalized after exercise. Furthermore, for 19.7 and 12.1% of the exercise-responsive proteins, corresponding changes in mRNA expression levels in muscle and fat, respectively, were shown. The protein CD300LG displayed consistent alterations in blood, muscle, and fat. Serum CD300LG exhibited positive associations with insulin sensitivity, and to angiogenesis-related gene expression in both muscle and fat. Furthermore, serum CD300LG was positively associated with physical activity and negatively associated with glucose levels in the UK Biobank. In this sample, the association between serum CD300LG and physical activity was significantly stronger in men than in women. Mendelian randomization analysis suggested potential causal relationships between levels of serum CD300LG and fasting glucose, 2 hr glucose after an oral glucose tolerance test, and HbA1c. Additionally, Cd300lg responded to exercise in a mouse model, and we observed signs of impaired glucose tolerance in male, but not female, Cd300lg knockout mice.
Conclusions: Our study identified several novel proteins in serum whose levels change in response to prolonged exercise and were significantly associated with body composition, liver fat, and glucose homeostasis. Serum CD300LG increased with physical activity and is a potential causal link to improved glucose levels. CD300LG may be a promising exercise biomarker and a therapeutic target in type 2 diabetes.
Funding: South-Eastern Norway Regional Health Authority, Simon Fougners Fund, Diabetesforbundet, Johan Selmer Kvanes' legat til forskning og bekjempelse av sukkersyke. The UK Biobank resource reference 53641. Australian National Health and Medical Research Council Investigator Grant (APP2017942). Australian Research Council Discovery Early Career Award (DE220101226). Research Council of Norway (Project grant: 325640 and Mobility grant: 287198). The Medical Student Research Program at the University of Oslo. Novo Nordisk Fonden Excellence Emerging Grant in Endocrinology and Metabolism 2023 (NNF23OC0082123).
Clinical trial number: clinicaltrials.gov: NCT01803568.

Keywords:  Mendelian randomization; Olink; diabetes; exercise; human; insulin resistance; medicine; proteomics

DOI:  https://doi.org/10.7554/eLife.96535
Pharmacol Ther. 2024 Aug 22. pii: S0163-7258(24)00130-X. [Epub ahead of print]262 108710

Targeting organ-specific mitochondrial dysfunction to improve biological aging.

Corina T Madreiter-Sokolowski, Ursula Hiden, Jelena Krstic, Katrin Panzitt, Martin Wagner, Christian Enzinger, Michael Khalil, Mahmoud Abdellatif, Ernst Malle, Tobias Madl, Elena Osto, Markus Schosserer, Christoph J Binder, Andrea Olschewski.

  In an aging society, unveiling new anti-aging strategies to prevent and combat aging-related diseases is of utmost importance. Mitochondria are the primary ATP production sites and key regulators of programmed cell death. Consequently, these highly dynamic organelles play a central role in maintaining tissue function, and mitochondrial dysfunction is a pivotal factor in the progressive age-related decline in cellular homeostasis and organ function. The current review examines recent advances in understanding the interplay between mitochondrial dysfunction and organ-specific aging. Thereby, we dissect molecular mechanisms underlying mitochondrial impairment associated with the deterioration of organ function, exploring the role of mitochondrial DNA, reactive oxygen species homeostasis, metabolic activity, damage-associated molecular patterns, biogenesis, turnover, and dynamics. We also highlight emerging therapeutic strategies in preclinical and clinical tests that are supposed to rejuvenate mitochondrial function, such as antioxidants, mitochondrial biogenesis stimulators, and modulators of mitochondrial turnover and dynamics. Furthermore, we discuss potential benefits and challenges associated with the use of these interventions, emphasizing the need for organ-specific approaches given the unique mitochondrial characteristics of different tissues. In conclusion, this review highlights the therapeutic potential of addressing mitochondrial dysfunction to mitigate organ-specific aging, focusing on the skin, liver, lung, brain, skeletal muscle, and lung, as well as on the reproductive, immune, and cardiovascular systems. Based on a comprehensive understanding of the multifaceted roles of mitochondria, innovative therapeutic strategies may be developed and optimized to combat biological aging and promote healthy aging across diverse organ systems.

Keywords:  Anti-aging strategies; Mitochondrial dysfunction; Organ-specific aging; ROS homeostasis; Therapeutic interventions

DOI:  https://doi.org/10.1016/j.pharmthera.2024.108710