bims-moremu 2024-01-14 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2024–01–14
34 papers selected by
Anna Vainshtein, Craft Science Inc.

Nuclear-localized androgen receptor content following resistance exercise training is associated with hypertrophy in males but not females.
Exercise induces tissue-specific adaptations to enhance cardiometabolic health.
The role of satellite cell-derived TRIM28 in mechanical load- and injury-induced myogenesis.
Yap/Taz activity is associated with increased expression of phosphoglycerate dehydrogenase that supports myoblast proliferation.
Augmented mitochondrial apoptotic signaling impairs C2C12 myoblast differentiation following cellular aging through sequential passaging.
Regulation of Satellite Cells Functions during Skeletal Muscle Regeneration: A Critical Step in Physiological and Pathological Conditions.
Voluntary wheel running improves molecular and functional deficits in a murine model of facioscapulohumeral muscular dystrophy.
Lipid peroxidation does not mediate muscle atrophy induced by PSD deficiency.
Unlocking the Potential of Obestatin: A Novel Peptide Intervention for Skeletal Muscle Regeneration and Prevention of Atrophy.
Exercise-induced vitamin D receptor and androgen receptor mediate inhibition of IL-6 and STAT3 in muscle.
Exercise microdosing for skeletal muscle health applications to spaceflight.
A century of exercise physiology: effects of muscle contraction and exercise on skeletal muscle Na+,K+-ATPase, Na+ and K+ ions, and on plasma K+ concentration-historical developments.
Low baseline ribosome-related gene expression and resistance training-induced declines in ribosome-related gene expression are associated with skeletal muscle hypertrophy in young men and women.
Predicting Myosin Heavy Chain Isoform from Post-Dissection Fiber Length in Human Skeletal Muscle Fibers.
17α-estradiol Alleviates High-Fat Diet-Induced Inflammatory and Metabolic Dysfunction in Skeletal Muscle of Male and Female Mice.
The RyR1 P3528S Substitution Alters Mouse Skeletal Muscle Contractile Properties and RyR1 Ion Channel Gating.
Remodeling of the human skeletal muscle proteome found after long-term endurance training but not after strength training.
Integrated Amino Acids and Transcriptome Analysis Reveals Arginine Transporter SLC7A2 Is a Novel Regulator of Myogenic Differentiation.
Ca2+ and force during dynamic contractions in mouse intact skeletal muscle fibers.
Running improves muscle mass by activating autophagic flux and inhibiting ubiquitination degradation in mdx mice.
Effects of Aging and Lifelong Aerobic Exercise on Expression of Innate Immune Components in Skeletal Muscle of Women.
Metabolic Changes during In Vivo Maturation of PSC-Derived Skeletal Myogenic Progenitors.
Successful Correction by Prime Editing of a Mutation in the RYR1 Gene Responsible for a Myopathy.
Small peptides: could they have a big role in metabolism and the response to exercise?
The mediating role of inflammaging between mitochondrial dysfunction and sarcopenia in aging: a review.
A single chemotherapy administration induces muscle atrophy, mitochondrial alterations and apoptosis in breast cancer patients.
Kinetic modeling of leucine-mediated signaling and protein metabolism in human skeletal muscle.
WAVE2 Is a Vital Regulator in Myogenic Differentiation of Progenitor Cells through the Mechanosensitive MRTFA-SRF Axis.
Oxidative stress and metabolism meet epigenetic modulation in physical exercise.
Biophysical reviews top five: voltage-dependent charge movement in nerve and muscle.
Dietary oleic acid intake increases the proportion of type 1 and 2X muscle fibers in mice.
The Therapeutic Potential of Ketones in Cardiometabolic Disease: Impact on Heart and Skeletal Muscle.
Characterization of NEB mutations in patients reveals novel nemaline myopathy disease mechanisms and omecamtiv mecarbil force effects.
Innovations in the Assessment of Skeletal Muscle Health: A Glimpse into the Future.

FASEB J. 2024 Jan 31. 38(2): e23403

Nuclear-localized androgen receptor content following resistance exercise training is associated with hypertrophy in males but not females.

Aidan A Hatt, Michael Kamal, Andrew I Mikhail, Stephen A Fortino, Mai Wageh, Dinesh Kumbhare, Gianni Parise.

  Androgen receptor (AR) content has been implicated in the differential response between high and low responders following resistance exercise training (RET). However, the influence of AR expression on acute skeletal muscle damage and whether it may influence the adaptive response to RET in females is poorly understood. Thus, the purpose of this exploratory examination was to 1) investigate changes in AR content during skeletal muscle repair and 2) characterize AR-mediated sex-based differences following RET. A skeletal muscle biopsy from the vastus lateralis was obtained from 26 healthy young men (n = 13) and women (n = 13) at baseline and following 300 eccentric kicks. Subsequently, participants performed 10 weeks of full-body RET and a final muscle biopsy was collected. In the untrained state, AR mRNA expression was associated with paired box protein-7 (PAX7) mRNA in males. For the first time in human skeletal muscle, we quantified AR content in the myofiber and localized to the nucleus where AR has been shown to trigger cellular outcomes related to growth. Upon eccentric damage, nuclear-associated AR (nAR) content increased (p < .05) in males and not females. Males with the greatest increase in cross-sectional area (CSA) post-RET had more (p < .05) nAR content than females with the greatest gain CSA. Collectively, skeletal muscle damage and RET increased AR protein, and both gene and hypertrophy measures revealed sex differences in relation to AR. These findings suggest that AR content but more importantly, nuclear localization, is a factor that differentiates RET-induced hypertrophy between males and females.

Keywords:  androgen receptor; eccentric damage; resistance exercise training; responder; satellite cell; sex-based differences; skeletal muscle hypertrophy

DOI:  https://doi.org/10.1096/fj.202301291RR
Cell Metab. 2023 Dec 29. pii: S1550-4131(23)00459-X. [Epub ahead of print]

Exercise induces tissue-specific adaptations to enhance cardiometabolic health.

Stephen P Ashcroft, Ben Stocks, Brendan Egan, Juleen R Zierath.

  The risk associated with multiple cancers, cardiovascular disease, diabetes, and all-cause mortality is decreased in individuals who meet the current recommendations for physical activity. Therefore, regular exercise remains a cornerstone in the prevention and treatment of non-communicable diseases. An acute bout of exercise results in the coordinated interaction between multiple tissues to meet the increased energy demand of exercise. Over time, the associated metabolic stress of each individual exercise bout provides the basis for long-term adaptations across tissues, including the cardiovascular system, skeletal muscle, adipose tissue, liver, pancreas, gut, and brain. Therefore, regular exercise is associated with a plethora of benefits throughout the whole body, including improved cardiorespiratory fitness, physical function, and glycemic control. Overall, we summarize the exercise-induced adaptations that occur within multiple tissues and how they converge to ultimately improve cardiometabolic health.

Keywords:  adaptations; cardiometabolic health; exercise; exercise physiology; exercise signaling; metabolism; multi-tissue

DOI:  https://doi.org/10.1016/j.cmet.2023.12.008
bioRxiv. 2023 Dec 29. pii: 2023.12.20.572566. [Epub ahead of print]

The role of satellite cell-derived TRIM28 in mechanical load- and injury-induced myogenesis.

Kuan-Hung Lin, Jamie E Hibbert, Jake L Lemens, Melissa M Torbey, Nathaniel D Steinert, Philip M Flejsierowicz, Kiley M Melka, Marcos Lares, Vijayasaradhi Setaluri, Troy A Hornberger.

Satellite cells are skeletal muscle stem cells that contribute to postnatal muscle growth, and they endow skeletal muscle with the ability to regenerate after a severe injury. Here we discovered that this myogenic potential of satellite cells requires a protein called tripartite motif-containing 28 (TRIM28). Unexpectedly, multiple lines of both in vitro and in vivo evidence revealed that the myogenic function of TRIM28 is not dependent on changes in the phosphorylation of its serine 473 residue. Moreover, the functions of TRIM28 were not mediated through the regulation of satellite cell proliferation or differentiation. Instead, our findings indicate that TRIM28 regulates the ability of satellite cells to progress through the process of fusion. Specifically, we discovered that TRIM28 controls the expression of a fusogenic protein called myomixer and concomitant fusion pore formation. Collectively, the outcomes of this study expose the framework of a novel regulatory pathway that is essential for myogenesis.

DOI: https://doi.org/10.1101/2023.12.20.572566
Cell Tissue Res. 2024 Jan 06.

Yap/Taz activity is associated with increased expression of phosphoglycerate dehydrogenase that supports myoblast proliferation.

Marius Meinhold, Sander Verbrugge, Andi Shi, Martin Schönfelder, Lore Becker, Richard T Jaspers, Peter S Zammit, Henning Wackerhage.

  In skeletal muscle, the Hippo effector Yap promotes satellite cell, myoblast, and rhabdomyoblast proliferation but prevents myogenic differentiation into multinucleated muscle fibres. We previously noted that Yap drives expression of the first enzyme of the serine biosynthesis pathway, phosphoglycerate dehydrogenase (Phgdh). Here, we examined the regulation and function of Phgdh in satellite cells and myoblasts and found that Phgdh protein increased during satellite cell activation. Analysis of published data reveal that Phgdh mRNA in mouse tibialis anterior muscle was highly expressed at day 3 of regeneration after cardiotoxin injection, when markers of proliferation are also robustly expressed and in the first week of synergist-ablated muscle. Finally, siRNA-mediated knockdown of PHGDH significantly reduced myoblast numbers and the proliferation rate. Collectively, our data suggest that Phgdh is a proliferation-enhancing metabolic enzyme that is induced when quiescent satellite cells become activated.

Keywords:  Myoblast; Phgdh; Phosphoglycerate dehydrogenase; Skeletal muscle; Taz; Yap

DOI:  https://doi.org/10.1007/s00441-023-03851-w
J Cell Physiol. 2024 Jan 11.

Augmented mitochondrial apoptotic signaling impairs C2C12 myoblast differentiation following cellular aging through sequential passaging.

Fasih A Rahman, Dylan J Hian-Cheong, Kristen Boonstra, Andrew Ma, James P Thoms, Anderson S Zago, Joe Quadrilatero.

  Aging is associated with the steady decline of several cellular processes. The loss of skeletal muscle mass, termed sarcopenia, is one of the major hallmarks of aging. Aged skeletal muscle exhibits a robust reduction in its regenerative capacity due to dysfunction (i.e., senescence, lack of self-renewal, and impaired differentiation) of resident muscle stem cells, called satellite cells. To replicate aging in vitro, immortalized skeletal muscle cells (myoblasts) can be treated with various agents to mimic age-related dysfunction; however, these come with their own set of limitations. In the present study, we used sequential passaging of mouse myoblasts to mimic impaired differentiation that is observed in aged skeletal muscle. Further, we investigated mitochondrial apoptotic mechanisms to better understand the impaired differentiation in these "aged" cells. Our data shows that sequential passaging (>20 passages) of myoblasts is accompanied with significant reductions in differentiation and elevated cell death. Furthermore, high-passage (HP) myoblasts exhibit greater mitochondrial-mediated apoptotic signaling through mitochondrial BAX translocation, CYCS and AIFM1 release, and caspase-9 activation. Finally, we show that inhibition of mitochondrial outer membrane permeability partly recovered differentiation in HP myoblasts. Together, our findings suggests that mitochondrial apoptotic signaling is a contributing factor to the diminished differentiation that is observed in aged myoblasts.

Keywords:  aging; apoptotic signaling; differentiation; high-passage; mitochondria; skeletal muscle

DOI:  https://doi.org/10.1002/jcp.31155
Int J Mol Sci. 2023 Dec 29. pii: 512. [Epub ahead of print]25(1):

Regulation of Satellite Cells Functions during Skeletal Muscle Regeneration: A Critical Step in Physiological and Pathological Conditions.

Giorgia Careccia, Laura Mangiavini, Federica Cirillo.

  Skeletal muscle regeneration is a complex process involving the generation of new myofibers after trauma, competitive physical activity, or disease. In this context, adult skeletal muscle stem cells, also known as satellite cells (SCs), play a crucial role in regulating muscle tissue homeostasis and activating regeneration. Alterations in their number or function have been associated with various pathological conditions. The main factors involved in the dysregulation of SCs' activity are inflammation, oxidative stress, and fibrosis. This review critically summarizes the current knowledge on the role of SCs in skeletal muscle regeneration. It examines the changes in the activity of SCs in three of the most common and severe muscle disorders: sarcopenia, muscular dystrophy, and cancer cachexia. Understanding the molecular mechanisms involved in their dysregulations is essential for improving current treatments, such as exercise, and developing personalized approaches to reactivate SCs.

Keywords:  cancer cachexia; muscular dystrophy; sarcopenia; satellite cells; skeletal muscle regeneration

DOI:  https://doi.org/10.3390/ijms25010512
iScience. 2024 Jan 19. 27(1): 108632

Voluntary wheel running improves molecular and functional deficits in a murine model of facioscapulohumeral muscular dystrophy.

Adam J Bittel, Daniel C Bittel, Heather Gordish-Dressman, Yi-Wen Chen.

  Endurance exercise training is beneficial for skeletal muscle health, but it is unclear if this type of exercise can target or correct the molecular mechanisms of facioscapulohumeral muscular dystrophy (FSHD). Using the FLExDUX4 murine model of FSHD characterized by chronic, low levels of pathological double homeobox protein 4 (DUX4) gene expression, we show that 6 weeks of voluntary, free wheel running improves running performance, strength, mitochondrial function, and sarcolemmal repair capacity, while slowing/reversing skeletal muscle fibrosis. These improvements are associated with restored transcriptional activity of gene networks/pathways regulating actin cytoskeletal signaling, vascular remodeling, inflammation, fibrosis, and muscle mass toward wild-type (WT) levels. However, FLExDUX4 mice exhibit blunted increases in mitochondrial content with training and persistent transcriptional overactivation of hypoxia, inflammatory, angiogenic, and cytoskeletal pathways. These results identify exercise-responsive and non-responsive molecular pathways in FSHD, while providing support for the use of endurance-type exercise as a non-invasive treatment option.

Keywords:  Biological sciences; Pathophysiology; Transcriptomics;

DOI:  https://doi.org/10.1016/j.isci.2023.108632
bioRxiv. 2023 Dec 23. pii: 2023.12.22.573082. [Epub ahead of print]

Lipid peroxidation does not mediate muscle atrophy induced by PSD deficiency.

Hiroaki Eshima, Jordan M Johnson, Katsuhiko Funai.

Mechanisms by which disuse promotes skeletal muscle atrophy is not well understood. We previously demonstrated that disuse reduces the abundance of mitochondrial phosphatidylethanolamine (PE) in skeletal muscle. Deletion of phosphatidylserine decarboxylase (PSD), an enzyme that generates mitochondrial PE, was sufficient to promote muscle atrophy. In this study, we tested the hypothesis that muscle atrophy induced by PSD deletion is driven by an accumulation of lipid hydroperoxides (LOOH). Mice with muscle-specific knockout of PSD (PSD-MKO) were crossed with glutathione peroxidase 4 (GPx4) transgenic mice (GPx4Tg) to suppress the accumulation of LOOH. However, PSD-MKO × GPx4Tg mice and PSD-MKO mice demonstrated equally robust loss of muscle mass. These results suggest that muscle atrophy induced by PSD deficiency is not driven by the accumulation of LOOH.

DOI: https://doi.org/10.1101/2023.12.22.573082
Mol Biotechnol. 2024 Jan 10.

Unlocking the Potential of Obestatin: A Novel Peptide Intervention for Skeletal Muscle Regeneration and Prevention of Atrophy.

Akash Mitra, Samanwita Mandal, Bipasha Bose, Sudheer Shenoy P.

  Obestatin is derived from the same gene as that of ghrelin and their functions were perceived to be antagonistic. Recent developments have shown that although they are known to have contradictory functions, effect of obestatin on skeletal muscle regeneration is similar to that of ghrelin. Obestatin works through a receptor called GPR39, a ghrelin and motilin family receptor and transduces signals in skeletal muscle similar to that of ghrelin. Not only there is a similarity in the receptor family, but also obestatin targets similar proteins and transcription factors as that of ghrelin (for example, FoxO family members) for salvaging skeletal muscle atrophy. Moreover, like ghrelin, obestatin also works by inducing the transcription of Pax7 which is required for muscle stem cell mobilisation. Hence, there are quite some evidences which points to the fact that obestatin can be purposed as a peptide intervention to prevent skeletal muscle wasting and induce myogenesis. This review elaborates these aspects of obestatin which can be further exploited and addressed to bring obestatin as a clinical intervention towards preventing skeletal muscle atrophy and sarcopenia.

Keywords:  Ghrelin; Muscle atrophy; Myogenesis; Obestatin; Signalling pathway

DOI:  https://doi.org/10.1007/s12033-023-01011-7
Biochem Biophys Rep. 2024 Mar;37 101621

Exercise-induced vitamin D receptor and androgen receptor mediate inhibition of IL-6 and STAT3 in muscle.

Seiji Hashimoto, Tatsuya Hosoi, Mitsutaka Yakabe, Shoya Matsumoto, Masayoshi Hashimoto, Masahiro Akishita, Sumito Ogawa.

   Background: Skeletal muscle produces interleukin-6 (IL-6) during exercise as a myokine. Although IL-6 is required for skeletal muscle regeneration, its action increases the expression of myostatin and other proteins involved in muscle atrophy, resulting in skeletal muscle atrophy. In this study, we clarified the effects exercise-induced vitamin D receptor (VDR) and androgen receptor (AR) expression on IL-6 and signal transducer and activator of transcription 3 (STAT3) in vivo and in vitro.
Method: C2C12 myotubes were subjected to electric pulse stimulation (EPS) in vitro. To evaluate VDR and AR function, a VDR/AR agonist and antagonist were administered before EPS to C2C12 myotubes. C57BL6 mice underwent 4 weeks of exercise. The expression levels of proteolytic-associated genes, including CCAAT/enhancer-binding protein delta (C/EBPδ) and myostatin, were measured by quantitative real-time polymerase chain reaction, and phosphorylated and total STAT3 levels were measured by Western blot analysis.
Result: The expression of VDR and AR mRNA was induced following EPS in C2C12 myotubes. IL-6 mRNA expression was also increased with a peak at 6 h after EPS and p-STAT3/STAT3 ratio reciprocally decreased. Although VDR/AR agonist administration decreased IL-6 mRNA expression and p-STAT3/STAT3 ratio, these two endpoints increased after treatment with VDR/AR antagonist, respectively. Exercise in mice also increased the expression of VDR/AR and IL-6 mRNA and decreased p-STAT3/STAT3 ratio.
Conclusion: Exercise-induced VDR and AR expression results in the suppression of IL-6 mRNA and STAT3 phosphorylation in skeletal muscle.

Keywords:  Androgen receptor; Interleukin-6; STAT3; Vitamin D receptor

DOI:  https://doi.org/10.1016/j.bbrep.2023.101621
J Appl Physiol (1985). 2024 Jan 11.

Exercise microdosing for skeletal muscle health applications to spaceflight.

Adam C Voss, Toby L Chambers, Kevin J Gries, Bozena Jemiolo, Ulrika Raue, Kiril Minchev, Gwenaelle Begue, Gary A Lee, Todd A Trappe, Scott W Trappe.

  Findings from a recent 70 day bedrest investigation suggested intermittent exercise testing in the control group may have served as a partial countermeasure for skeletal muscle size, function, and fiber-type shifts. The purpose of the current study was to investigate the metabolic and skeletal muscle molecular responses to the testing protocols. Eight males (29±2y) completed muscle power (6x4 sec; peak muscle power: 1369±86W) and VO2max (13±1min; 3.2±0.2L/min) tests on specially designed supine cycle ergometers during two separate trials. Blood catecholamines and lactate were measured pre, immediately post, and 4h postexercise. Muscle homogenate and muscle fiber-type specific (myosin heavy chain (MHC) I and MHC IIa) mRNA levels of exercise markers (myostatin, IκBα, myogenin, MuRF-1, ABRA, RRAD, Fn14, PDK4) and MHC I, IIa, and IIx were measured from vastus lateralis muscle biopsies obtained pre and 4h postexercise. The muscle power test altered (p≤0.05) norepinephrine (+124%), epinephrine (+145%), lactate (+300%), and muscle homogenate mRNA (IκBα, myogenin, MuRF-1, RRAD, Fn14). The VO2max test altered (p≤0.05) norepinephrine (+1394%), epinephrine (+1412%), lactate (+736%), and muscle homogenate mRNA (myostatin, IκBα, myogenin, MuRF-1, ABRA, RRAD, Fn14, PDK4). In general, both tests influenced MHC IIa muscle fibers more than MHC I with respect to the number of genes that responded and the magnitude of response. Both tests also influenced MHC mRNA expression in a muscle fiber-type specific manner. These findings provide unique insights into the adaptive response of skeletal muscle to small doses of exercise and could help shape exercise countermeasures for astronauts and Earth-based populations (e.g., aging individuals).

Keywords:  countermeasures; exercise; microgravity; muscle; weightlessness

DOI:  https://doi.org/10.1152/japplphysiol.00491.2023
Eur J Appl Physiol. 2024 Jan 11.

A century of exercise physiology: effects of muscle contraction and exercise on skeletal muscle Na+,K+-ATPase, Na+ and K+ ions, and on plasma K+ concentration-historical developments.

Michael J McKenna, Jean-Marc Renaud, Niels Ørtenblad, Kristian Overgaard.

  This historical review traces key discoveries regarding K+ and Na+ ions in skeletal muscle at rest and with exercise, including contents and concentrations, Na+,K+-ATPase (NKA) and exercise effects on plasma [K+] in humans. Following initial measures in 1896 of muscle contents in various species, including humans, electrical stimulation of animal muscle showed K+ loss and gains in Na+, Cl- and H20, then subsequently bidirectional muscle K+ and Na+ fluxes. After NKA discovery in 1957, methods were developed to quantify muscle NKA activity via rates of ATP hydrolysis, Na+/K+ radioisotope fluxes, [3H]-ouabain binding and phosphatase activity. Since then, it became clear that NKA plays a central role in Na+/K+ homeostasis and that NKA content and activity are regulated by muscle contractions and numerous hormones. During intense exercise in humans, muscle intracellular [K+] falls by 21 mM (range - 13 to - 39 mM), interstitial [K+] increases to 12-13 mM, and plasma [K+] rises to 6-8 mM, whilst post-exercise plasma [K+] falls rapidly, reflecting increased muscle NKA activity. Contractions were shown to increase NKA activity in proportion to activation frequency in animal intact muscle preparations. In human muscle, [3H]-ouabain-binding content fully quantifies NKA content, whilst the method mainly detects α2 isoforms in rats. Acute or chronic exercise affects human muscle K+, NKA content, activity, isoforms and phospholemman (FXYD1). Numerous hormones, pharmacological and dietary interventions, altered acid-base or redox states, exercise training and physical inactivity modulate plasma [K+] during exercise. Finally, historical research approaches largely excluded female participants and typically used very small sample sizes.

Keywords:  Exercise; FXYD; Fatigue; Na+, K+-pump; Plasma; Potassium; Skeletal muscle; Sodium

DOI:  https://doi.org/10.1007/s00421-023-05335-9
J Cell Physiol. 2024 Jan 12.

Low baseline ribosome-related gene expression and resistance training-induced declines in ribosome-related gene expression are associated with skeletal muscle hypertrophy in young men and women.

Alex Brown, Gianni Parise, Aaron C Q Thomas, Sean Y Ng, Chris McGlory, Stuart M Phillips, Dinesh Kumbhare, Sophie Joanisse.

  Ribosomes are essential cellular machinery for protein synthesis. It is hypothesised that ribosome content supports muscle growth and that individuals with more ribosomes have greater increases in muscle size following resistance training (RT). Aerobic conditioning (AC) also elicits distinct physiological adaptations; however, no measures of ribosome content following AC have been conducted. We used ribosome-related gene expression as a proxy measure for ribosome content and hypothesised that AC and RT would increase ribosome-related gene expression. Fourteen young men and women performed 6 weeks of single-legged AC followed by 10 weeks of double-legged RT. Muscle biopsies were taken following AC and following RT in the aerobically conditioned (AC+RT) and unconditioned (RT) legs. No differences in regulatory genes (Ubf, Cyclin D1, Tif-1a and Polr-1b) involved in ribosomal biogenesis or ribosomal RNA (45S, 5.8S, 18S and 28S rRNAs) expression were observed following AC and RT, except for c-Myc (RT > AC+RT) and 5S rRNA (RT < AC+RT at pre-RT) with 18S external transcribed spacer and 5.8S internal transcribed spacer expression decreasing from pre-RT to post-RT in the RT leg only. When divided for change in leg-lean soft tissue mass (ΔLLSTM) following RT, legs with the greatest ΔLLSTM had lower expression in 11/13 measured ribosome-related genes before RT and decreased expression in 9/13 genes following RT. These results indicate that AC and RT did not increase ribosome-related gene expression. Contrary to previous research, the greatest increase in muscle mass was associated with lower changes in ribosome-related gene expression over the course of the 10-week training programme. This may point to the importance of translational efficiency rather than translational capacity (i.e. ribosome content) in mediating long-term exercise-induced adaptations in skeletal muscle.

Keywords:  aerobic conditioning; resistance training; ribosome; skeletal muscle

DOI:  https://doi.org/10.1002/jcp.31182
Am J Physiol Cell Physiol. 2024 Jan 08.

Predicting Myosin Heavy Chain Isoform from Post-Dissection Fiber Length in Human Skeletal Muscle Fibers.

Grace E Privett, Austin W Ricci, Julissa Ortiz-Delatorre, Damien M Callahan.

  Experimental techniques in single human skeletal muscle cells require manual dissection. Unlike other mammalian species, human skeletal muscle is characterized by a heterogeneous mixture of myosin heavy chain (MHC) isoforms, typically used to define "fiber type", which profoundly influences cellular function. Therefore, it is beneficial to predict MHC isoform at the time of dissection, facilitating a more balanced fiber-type distribution from a potentially imbalanced sample. Although researchers performing single fiber dissection report predicting fiber-type based on mechanical properties of fibers upon dissection, a rigorous examination of this approach has not been performed. Therefore, we measured normalized fiber length (expressed as a % of length of the bundle from which the fiber was dissected) in single fibers immediately following dissection. 668 individual fibers were dissected from muscle tissue samples from healthy, young adults to assess whether this characteristic could differentiate fibers containing MHC I ("slow" fiber type) or not ("fast" fiber type). Using receiver operator characteristic (ROC) curves, we found that differences in normalized fiber length (114 ± 13%, MHC I; 124 ± 17%, MHC IIA, p < 0.01) could be used to predict fiber type with excellent reliability (area under the curve = 0.72). We extended these analyses to include older adults (2 females, 1 male) to demonstrate the durability of this approach in fibers with likely different morphology and mechanical characteristics. We report that MHC isoform expression in human skeletal muscle fibers can be predicted at the time of dissection, regardless of origin.

Keywords:  MHC; ROC; fiber length; skeletal muscle

DOI:  https://doi.org/10.1152/ajpcell.00700.2023
Am J Physiol Endocrinol Metab. 2024 Jan 10.

17α-estradiol Alleviates High-Fat Diet-Induced Inflammatory and Metabolic Dysfunction in Skeletal Muscle of Male and Female Mice.

Matthew P Bubak, Shivani N Mann, Agnieszka K Borowik, Atul Pranay, Albert Batushansky, Ivo Vieira de Sousa Neto, Samim A Ali Mondal, Stephen M Doidge, Arik Davidyan, Marcelina M Szczygiel, Frederick F Peelor Iii, Sandra Rigsby, Matle E Broomfield, Charles I Lacy, Heather C Rice, Michael B Stout, Benjamin F Miller.

  17α-estradiol (17α-E2) is a naturally occurring non-feminizing diastereomer of 17β-estradiol that has lifespan extending effects in rodent models. To date studies of the systemic and tissue-specific benefits of 17α-E2 have largely focused on liver, brain, and white adipose tissue with far less focus on skeletal muscle. Skeletal muscle has an important role in metabolic and age-related disease. Therefore, this study aimed to determine if 17α-E2 treatment has positive, tissue-specific effects in skeletal muscle during a high fat feeding. We hypothesized that male, but not female, mice, would benefit from 17α-E2 treatment during a HFD with changes in the mitochondrial proteome to support lipid oxidation and subsequent reductions in DAG and ceramide content. To test this hypothesis, we used a multi-omics approach to determine changes in lipotoxic lipid intermediates, metabolites, and proteins related to metabolic homeostasis. Unexpectedly, we found that 17α-E2 had marked but different beneficial effects within each sex. In male mice, we show that 17α-E2 alleviates HFD-induced metabolic detriments of skeletal muscle by reducing the accumulation of diacylglycerol (DAGs) and ceramides, inflammatory cytokine levels, and altered the abundance of most of the proteins related to lipolysis and beta-oxidation. Similar to male mice, 17α-E2 treatment reduced fat mass while protecting muscle mass in female mice but had little muscle inflammatory cytokine levels. While female mice were resistant to HFD induced changes in DAGs, 17α-E2 treatment induced the upregulation six DAG species. In female mice, 17α-E2 treatment changed the relative abundance of proteins involved in lipolysis, beta-oxidation, as well as structural and contractile proteins but to a smaller extent than male mice. These data demonstrate metabolic benefits of 17α-E2 in skeletal muscle of male and female mice and contribute to the growing literature of the use of 17α-E2 for multi-tissue healthspan benefits.

Keywords:  Deuterium Oxide; Estrogen; Lipids; Metabolism; Obesity

DOI:  https://doi.org/10.1152/ajpendo.00215.2023
Int J Mol Sci. 2023 Dec 28. pii: 434. [Epub ahead of print]25(1):

The RyR1 P3528S Substitution Alters Mouse Skeletal Muscle Contractile Properties and RyR1 Ion Channel Gating.

Chris G Thekkedam, Travis L Dutka, Chris Van der Poel, Gaetan Burgio, Angela F Dulhunty.

  The recessive Ryanodine Receptor Type 1 (RyR1) P3527S mutation causes mild muscle weakness in patients and increased resting cytoplasmic [Ca2+] in transformed lymphoblastoid cells. In the present study, we explored the cellular/molecular effects of this mutation in a mouse model of the mutation (RyR1 P3528S). The results were obtained from 73 wild type (WT/WT), 82 heterozygous (WT/MUT) and 66 homozygous (MUT/MUT) mice with different numbers of observations in individual data sets depending on the experimental protocol. The results showed that WT/MUT and MUT/MUT mouse strength was less than that of WT/WT mice, but there was no difference between genotypes in appearance, weight, mobility or longevity. The force frequency response of extensor digitorum longus (EDL) and soleus (SOL) muscles from WT/MUT and MUT/MUT mice was shifter to higher frequencies. The specific force of EDL muscles was reduced and Ca2+ activation of skinned fibres shifted to a lower [Ca2+], with an increase in type I fibres in EDL muscles and in mixed type I/II fibres in SOL muscles. The relative activity of RyR1 channels exposed to 1 µM cytoplasmic Ca2+ was greater in WT/MUT and MUT/MUT mice than in WT/WT mice. We suggest the altered RyR1 activity due to the P2328S substitution could increase resting [Ca2+] in muscle fibres, leading to changes in fibre type and contractile properties.

Keywords:  Ca2+ activation of skinned muscle fibres; RyR1 P3528S substitution; fibre-type composition; mouse model; muscle contractile properties; ryanodine receptor; single ryanodine receptor activity

DOI:  https://doi.org/10.3390/ijms25010434
iScience. 2024 Jan 19. 27(1): 108638

Remodeling of the human skeletal muscle proteome found after long-term endurance training but not after strength training.

Eric B Emanuelsson, Muhammad Arif, Stefan M Reitzner, Sean Perez, Maléne E Lindholm, Adil Mardinoglu, Carsten Daub, Carl Johan Sundberg, Mark A Chapman.

  Exercise training has tremendous systemic tissue-specific health benefits, but the molecular adaptations to long-term exercise training are not completely understood. We investigated the skeletal muscle proteome of highly endurance-trained, strength-trained, and untrained individuals and performed exercise- and sex-specific analyses. Of the 6,000+ proteins identified, >650 were differentially expressed in endurance-trained individuals compared with controls. Strikingly, 92% of the shared proteins with higher expression in both the male and female endurance groups were known mitochondrial. In contrast to the findings in endurance-trained individuals, minimal differences were found in strength-trained individuals and between females and males. Lastly, a co-expression network and comparative literature analysis revealed key proteins and pathways related to the health benefits of exercise, which were primarily related to differences in mitochondrial proteins. This network is available as an interactive database resource where investigators can correlate clinical data with global gene and protein expression data for hypothesis generation.

Keywords:  Biological sciences; Health sciences; Medicine; Omics

DOI:  https://doi.org/10.1016/j.isci.2023.108638
Int J Mol Sci. 2023 Dec 20. pii: 95. [Epub ahead of print]25(1):

Integrated Amino Acids and Transcriptome Analysis Reveals Arginine Transporter SLC7A2 Is a Novel Regulator of Myogenic Differentiation.

Tiane Huang, Jing Zhou, Benhui Wang, Xiang Wang, Wanli Xiao, Mengqi Yang, Yan Liu, Qiquan Wang, Yang Xiang, Xinqiang Lan.

  Skeletal muscle differentiation is a precisely coordinated process. While many of the molecular details of myogenesis have been investigated extensively, the dynamic changes and functions of amino acids and related transporters remain unknown. In this study, we conducted a comprehensive analysis of amino acid levels during different time points of C2C12 myoblast differentiation using high-performance liquid chromatography (HPLC). Our findings revealed that the levels of most amino acids exhibited an initial increase at the onset of differentiation, reaching their peak typically on the fourth or sixth day, followed by a decline on the eighth day. Particularly, arginine and branched-chain amino acids showed a prominent increase during this period. Furthermore, we used RNA-seq analysis to show that the gene encoding the arginine transporter, Slc7a2, is significantly upregulated during differentiation. Knockdown of Slc7a2 gene expression resulted in a significant decrease in myoblast proliferation and led to a reduction in the expression levels of crucial myogenic regulatory factors, hindering the process of myoblast differentiation, fusion, and subsequent myotube formation. Lastly, we assessed the expression level of Slc7a2 during aging in humans and mice and found an upregulation of Slc7a2 expression during the aging process. These findings collectively suggest that the arginine transporter SLC7A2 plays a critical role in facilitating skeletal muscle differentiation and may hold potential as a therapeutic target for sarcopenia.

Keywords:  SLC7A2; amino acids; myogenic differentiation; sarcopenia; transporter

DOI:  https://doi.org/10.3390/ijms25010095
Sci Rep. 2024 01 06. 14(1): 689

Ca2+ and force during dynamic contractions in mouse intact skeletal muscle fibers.

Atsuki Fukutani, Håkan Westerblad, Kent Jardemark, Joseph Bruton.

Muscle fiber force production is determined by the excitation frequency of motor nerves, which induce transient increases in cytoplasmic free Ca2+ concentration ([Ca2+]i) and the force-generating capacity of the actomyosin cross-bridges. Previous studies suggest that, in addition to altered cross-bridge properties, force changes during dynamic (concentric or eccentric) contraction might be affected by Ca2+-dependent components. Here we investigated this by measuring [Ca2+]i and force in mouse muscle fibers undergoing isometric, concentric, and eccentric contractions. Intact single muscle fibers were dissected from the flexor digitorum brevis muscle of mice. Fibers were electrically activated isometrically at 30-100 Hz and after reaching the isometric force plateau, they were actively shortened or stretched. We calculated the ratio (relative changes) in force and [Ca2+]i attained in submaximal (30 Hz) and near-maximal (100 Hz) contractions under isometric or dynamic conditions. Tetanic [Ca2+]i was similar during isometric, concentric and eccentric phases of contraction at given stimulation frequencies while the forces were clearly different depending on the contraction types. The 30/100 Hz force ratio was significantly lower in the concentric (44.1 ± 20.3%) than in the isometric (50.3 ± 20.4%) condition (p = 0.005), whereas this ratio did not differ between eccentric and isometric conditions (p = 0.186). We conclude that the larger force decrease by decreasing the stimulation frequency during concentric than during isometric contraction is caused by decreased myofibrillar Ca2+ sensitivity, not by the decreased [Ca2+]i.

DOI: https://doi.org/10.1038/s41598-023-51100-5
Gene. 2024 Jan 05. pii: S0378-1119(24)00016-7. [Epub ahead of print]899 148136

Running improves muscle mass by activating autophagic flux and inhibiting ubiquitination degradation in mdx mice.

Shanyao Zhou, Si Lei, Yanling She, Huacai Shi, Yang Li, Xin Zhou, Rui Chen.

   BACKGROUND: Exercise therapy can improve muscle mass, strengthen muscle and cardiorespiratory function, and may be an excellent adjunctive treatment option for Duchenne muscular dystrophy.
METHODS: This article investigates the effects of 10 weeks of treadmill training on skeletal muscle in control and mdx mice. Hematoxylin and eosin (H&E) staining was used to detect the morphometry of skeletal muscle; the grip strength test, suspension test, and rotarod test were used to detect limb muscle strength of mice, and Aurora Scientific Instruments were used to detect in vivo Muscle Stimulation Measuring Maximum Force of pre-fatigue and post-fatigue. The expression levels of myogenic proteins, ubiquitination markers, autophagy pathway proteins, and the proportion of different muscle fiber types were detected.
RESULTS: The experimental results show that running exercise can significantly improve the muscle mass of mdx mice, promote muscle strength, endurance, and anti-fatigue ability, reverse the pathological state of skeletal muscle destruction in mdx mice, and promote muscle regeneration. WB experiments showed that running inhibited the ubiquitination and degradation of muscle protein in mdx mice, inhibited AKT activation, decreased phosphorylated FoxO1 and FoxO3a, and restored the suppressed autophagic flux. Running enhances muscle strength and endurance by comprehensively promoting the expression of Myh1/2/4/7 fast and slow muscle fibers in mdx mice.
CONCLUSIONS: Running can inhibit the degradation of muscle protein in mdx mice, and promote the reuse and accumulation of proteins, thereby slowing down muscle loss. Running improves skeletal muscle mass by activating autophagic flux and inhibiting ubiquitination degradation in mdx mice.

Keywords:  Autophagy; Duchenne muscular dystrophy; Exercise; Mdx mouse; Muscle; Ubiquitination

DOI:  https://doi.org/10.1016/j.gene.2024.148136
J Appl Physiol (1985). 2024 Jan 11.

Effects of Aging and Lifelong Aerobic Exercise on Expression of Innate Immune Components in Skeletal Muscle of Women.

Ryan K Perkins, Kaleen M Lavin, Ulrika Raue, Bozena Jemiolo, Scott W Trappe, Todd A Trappe.

  This study examined the effects of aging and lifelong aerobic exercise on innate immune system components in skeletal muscle of healthy women in the basal state and after an unaccustomed resistance exercise (RE) challenge. We also made exploratory between-sex comparisons to our previous report on men. Three groups of women were studied: young exercisers (YE, n=10, 25±1y, VO2max: 44±2mL/kg/min), lifelong aerobic exercisers with a 48±2y training history (LLE, n=7, 72±2y, VO2max: 26±2mL/kg/min), and old healthy non-exercisers (OH, n=10, 75±1y, VO2max: 18±1mL/kg/min). Ten Toll-like receptors (TLR)1-10, TLR adaptors (Myd88, TRIF), and NFκB pathway components (IκBα, IKKβ) were assessed at the mRNA level in vastus lateralis biopsies before and 4h after RE (3x10 repetitions, 70% 1RM). Basal TLR1-10 expression was minimally influenced by age or LLE in women (TLR9 only; OH>YE, +43%, P<0.05; OH>LLE, +30%, P<0.10) and was on average 24% higher in women vs men. Similarly, basal adaptor expression was not influenced (P>0.05) by age or LLE in women, but was on average 26% higher (Myd88) and 23% lower (TRIF) in women vs men. RE induced changes in women, independent of group, in TLR3, TLR4, TLR6 (~2.1-fold, P<0.05), Myd88 (~1.2-fold, P<0.10), and IκBα (~0.3-fold, P<0.05). While there were some similar RE responses in men (TLR4: 2.1-fold, Myd88: 1.2-fold, IκBα: 0.4-fold), several components responded only in men to RE (TLR1, TLR8, TRIF, IKKβ). Our findings support the sexual dimorphism of immunity, with women having greater basal skeletal muscle TLR expression and a differential response to unaccustomed exercise than men.

Keywords:  TLR; aging; innate immunity; lifelong exercise; skeletal muscle

DOI:  https://doi.org/10.1152/japplphysiol.00444.2023
Cells. 2023 Dec 29. pii: 76. [Epub ahead of print]13(1):

Metabolic Changes during In Vivo Maturation of PSC-Derived Skeletal Myogenic Progenitors.

Phablo Abreu, Bayardo I Garay, Travis Nemkov, Aline M S Yamashita, Rita C R Perlingeiro.

  In vitro-generated pluripotent stem cell (PSC)-derived Pax3-induced (iPax3) myogenic progenitors display an embryonic transcriptional signature, but upon engraftment, the profile of re-isolated iPax3 donor-derived satellite cells changes toward similarity with postnatal satellite cells, suggesting that engrafted PSC-derived myogenic cells remodel their transcriptional signature upon interaction within the adult muscle environment. Here, we show that engrafted myogenic progenitors also remodel their metabolic state. Assessment of oxygen consumption revealed that exposure to the adult muscle environment promotes overt changes in mitochondrial bioenergetics, as shown by the substantial suppression of energy requirements in re-isolated iPax3 donor-derived satellite cells compared to their in vitro-generated progenitors. Mass spectrometry-based metabolomic profiling further confirmed the relationship of engrafted iPax3 donor-derived cells to adult satellite cells. The fact that in vitro-generated myogenic progenitors remodel their bioenergetic signature upon in vivo exposure to the adult muscle environment may have important implications for therapeutic applications.

Keywords:  in vitro; in vivo; metabolism; myogenic progenitors; pluripotent stem cells; satellite cells

DOI:  https://doi.org/10.3390/cells13010076
Cells. 2023 Dec 22. pii: 31. [Epub ahead of print]13(1):

Successful Correction by Prime Editing of a Mutation in the RYR1 Gene Responsible for a Myopathy.

Kelly Godbout, Joël Rousseau, Jacques P Tremblay.

  We report the first correction from prime editing a mutation in the RYR1 gene, paving the way to gene therapies for RYR1-related myopathies. The RYR1 gene codes for a calcium channel named Ryanodine receptor 1, which is expressed in skeletal muscle fibers. The failure of this channel causes muscle weakness in patients, which leads to motor disabilities. Currently, there are no effective treatments for these diseases, which are mainly caused by point mutations. Prime editing allows for the modification of precise nucleotides in the DNA. Our results showed a 59% correction rate of the T4709M mutation in the RYR1 gene in human myoblasts by RNA delivery of the prime editing components. It is to be noted that T4709M is recessive and, thus, persons having a heterozygous mutation are healthy. These results are the first demonstration that correcting mutations in the RYR1 gene is possible.

Keywords:  CRISPR/Cas9; RYR1 gene; RYR1-related diseases; gene editing; gene therapy; mutations; neuromuscular diseases; prime editing

DOI:  https://doi.org/10.3390/cells13010031
J Physiol. 2024 Jan 09.

Small peptides: could they have a big role in metabolism and the response to exercise?

Muhammed M Atakan, İbrahim Türkel, Berkay Özerkliğ, Şükran N Koşar, Dale F Taylor, Xu Yan, David J Bishop.

  Exercise is a powerful non-pharmacological intervention for the treatment and prevention of numerous chronic diseases. Contracting skeletal muscles provoke widespread perturbations in numerous cells, tissues and organs, which stimulate multiple integrated adaptations that ultimately contribute to the many health benefits associated with regular exercise. Despite much research, the molecular mechanisms driving such changes are not completely resolved. Technological advancements beginning in the early 1960s have opened new avenues to explore the mechanisms responsible for the many beneficial adaptations to exercise. This has led to increased research into the role of small peptides (<100 amino acids) and mitochondrially derived peptides in metabolism and disease, including those coded within small open reading frames (sORFs; coding sequences that encode small peptides). Recently, it has been hypothesized that sORF-encoded mitochondrially derived peptides and other small peptides play significant roles as exercise-sensitive peptides in exercise-induced physiological adaptation. In this review, we highlight the discovery of mitochondrially derived peptides and newly discovered small peptides involved in metabolism, with a specific emphasis on their functions in exercise-induced adaptations and the prevention of metabolic diseases. In light of the few studies available, we also present data on how both single exercise sessions and exercise training affect expression of sORF-encoded mitochondrially derived peptides. Finally, we outline numerous research questions that await investigation regarding the roles of mitochondrially derived peptides in metabolism and prevention of various diseases, in addition to their roles in exercise-induced physiological adaptations, for future studies.

Keywords:  exercise; metabolism; mitochondria; mitochondrially derived peptides; small open reading frames

DOI:  https://doi.org/10.1113/JP283214
Am J Clin Exp Immunol. 2023 ;12(6): 109-126

The mediating role of inflammaging between mitochondrial dysfunction and sarcopenia in aging: a review.

Xin Xu, Zixing Wen.

Sarcopenia, characterized by the insidious reduction of skeletal muscle mass and strength, detrimentally affects the quality of life in elderly cohorts. Present therapeutic strategies are confined to physiotherapeutic interventions, signaling a critical need for elucidation of the etiological underpinnings to facilitate the development of innovative pharmacotherapies. Recent scientific inquiries have associated mitochondrial dysfunction and inflammation with the etiology of sarcopenia. Mitochondria are integral to numerous fundamental cellular processes within muscle tissue, including but not limited to apoptosis, autophagy, signaling via reactive oxygen species, and the maintenance of protein equilibrium. Deviations in mitochondrial dynamics, coupled with compromised oxidative capabilities, autophagic processes, and protein equilibrium, result in disturbances to muscular architecture and functionality. Mitochondrial dysfunction is particularly detrimental as it diminishes oxidative phosphorylation, escalates apoptotic activity, and hinders calcium homeostasis within muscle cells. Additionally, deleterious feedback loops of deteriorated respiration, exacerbated oxidative injury, and diminished quality control mechanisms precipitate the acceleration of muscular senescence. Notably, mitochondria exhibiting deficient energetic metabolism are pivotal in precipitating the shift from normative muscle aging to a pathogenic state. This analytical review meticulously examines the complex interplay between mitochondrial dysfunction, persistent inflammation, and the pathogenesis of sarcopenia. It underscores the imperative to alleviate inflammation and amend mitochondrial anomalies within geriatric populations as a strategy to forestall and manage sarcopenia. An initial overview provides a succinct exposition of sarcopenia and its clinical repercussions. The discourse then progresses to an examination of the direct correlation between mitochondrial dysfunction and the genesis of sarcopenia. Concomitantly, it accentuates potential synergistic effects between inflammatory responses and mitochondrial insufficiencies during the aging of skeletal muscle, thereby casting light upon emergent therapeutic objectives. In culmination, this review distills the prevailing comprehension of the mitochondrial and inflammatory pathways implicated in sarcopenia and delineates extant lacunae in knowledge to orient subsequent scientific inquiry.

Keywords: Sarcopenia; inflammaging; mitochondrial dysfunction
J Cachexia Sarcopenia Muscle. 2024 Jan 06.

A single chemotherapy administration induces muscle atrophy, mitochondrial alterations and apoptosis in breast cancer patients.

Joris Mallard, Elyse Hucteau, Laura Bender, Fabien Moinard-Butot, Emma Rochelle, Lauréline Boutonnet, Antoine Grandperrin, Roland Schott, Carole Pflumio, Philippe Trensz, Michal Kalish-Weindling, Anne-Laure Charles, Bernard Gény, Fabrice Favret, Xavier Pivot, Thomas J Hureau, Allan F Pagano.

   BACKGROUND: Breast cancer patients are commonly treated with sequential administrations of epirubicin-cyclophosphamide (EC) and paclitaxel (TAX). The chronic effect of this treatment induces skeletal muscle alterations, but the specific effect of each chemotherapy agent is unknown. This study aimed to investigate the effect of EC or TAX administration on skeletal muscle homeostasis in breast cancer patients.
METHODS: Twenty early breast cancer patients undergoing EC followed by TAX chemotherapies were included. Two groups of 10 women were established and performed vastus lateralis skeletal muscle biopsies either before the first administration (pre) of EC (50 ± 14 years) or TAX (50 ± 16 years) and 4 days later (post). Mitochondrial respiratory capacity recording, reactive oxygen species production, western blotting and histological analyses were performed.
RESULTS: Decrease in muscle fibres cross-sectional area was only observed post-EC (-25%; P < 0.001), associated with a reduction in mitochondrial respiratory capacity for the complex I (CI)-linked substrate state (-32%; P = 0.001), oxidative phosphorylation (OXPHOS) by CI (-35%; P = 0.002), CI&CII (-26%; P = 0.022) and CII (-24%; P = 0.027). If H2 O2 production was unchanged post-EC, an increase was observed post-TAX for OXPHOS by CII (+25%; P = 0.022). We found a decrease in makers of mitochondrial content, as shown post-EC by a decrease in the protein levels of citrate synthase (-53%; P < 0.001) and VDAC (-39%; P < 0.001). Despite no changes in markers of mitochondrial fission, a decrease in the expression of a marker of mitochondrial inner-membrane fusion was found post-EC (OPA1; -60%; P < 0.001). We explored markers of mitophagy and found reductions post-EC in the protein levels of PINK1 (-63%; P < 0.001) and Parkin (-56%; P = 0.005), without changes post-TAX. An increasing trend in Bax protein level was found post-EC (+96%; P = 0.068) and post-TAX (+77%; P = 0.073), while the Bcl-2 level was decreased only post-EC (-52%; P = 0.007). If an increasing trend in TUNEL-positive signal was observed post-EC (+68%; P = 0.082), upregulation was highlighted post-TAX (+86%; P < 0.001), suggesting activation of the apoptosis process.
CONCLUSIONS: We demonstrated that a single administration of EC induced, in only 4 days, skeletal muscle atrophy and mitochondrial alterations in breast cancer patients. These alterations were characterized by reductions in mitochondrial function and content as well as impairment of mitochondrial dynamics and an increase in apoptosis. TAX administration did not worsen these alterations as this group had already received EC during the preceding weeks. However, it resulted in an increased apoptosis, likely in response to the increased H2 O2 production.

Keywords:  Anthracycline-cyclophosphamide; Mitochondria; Mitochondrial respiration; Muscle biopsies; Skeletal muscle deconditioning; Taxanes

DOI:  https://doi.org/10.1002/jcsm.13414
iScience. 2024 Jan 19. 27(1): 108634

Kinetic modeling of leucine-mediated signaling and protein metabolism in human skeletal muscle.

Taylor J McColl, David C Clarke.

  Skeletal muscle protein levels are governed by the relative rates of muscle protein synthesis (MPS) and breakdown (MPB). The mechanisms controlling these rates are complex, and their integrated behaviors are challenging to study through experiments alone. The purpose of this study was to develop and analyze a kinetic model of leucine-mediated mTOR signaling and protein metabolism in the skeletal muscle of young adults. Our model amalgamates published cellular-level models of the IRS1-PI3K-Akt-mTORC1 signaling system and of skeletal-muscle leucine kinetics with physiological-level models of leucine digestion and transport and insulin dynamics. The model satisfactorily predicts experimental data from diverse leucine feeding protocols. Model analysis revealed that total levels of p70S6K are a primary determinant of MPS, insulin signaling substantially affects muscle net protein balance via its effects on MPB, and p70S6K-mediated feedback of mTORC1 signaling reduces MPS in a dose-dependent manner.

Keywords:  Biological sciences; Protein

DOI:  https://doi.org/10.1016/j.isci.2023.108634
Cells. 2023 Dec 20. pii: 9. [Epub ahead of print]13(1):

WAVE2 Is a Vital Regulator in Myogenic Differentiation of Progenitor Cells through the Mechanosensitive MRTFA-SRF Axis.

Mai Thi Nguyen, Quoc Kiet Ly, Hyun-Jung Kim, Wan Lee.

  Skeletal myogenesis is an intricate process involving the differentiation of progenitor cells into myofibers, which is regulated by actin cytoskeletal dynamics and myogenic transcription factors. Although recent studies have demonstrated the pivotal roles of actin-binding proteins (ABPs) as mechanosensors and signal transducers, the biological significance of WAVE2 (Wiskott-Aldrich syndrome protein family member 2), an ABP essential for actin polymerization, in myogenic differentiation of progenitor cells has not been investigated. Our study provides important insights into the regulatory roles played by WAVE2 in the myocardin-related transcription factor A (MRTFA)-serum response factor (SRF) signaling axis and differentiation of myoblasts. We demonstrate that WAVE2 expression is induced during myogenic differentiation and plays a pivotal role in actin cytoskeletal remodeling in C2C12 myoblasts. Knockdown of WAVE2 in C2C12 cells reduced filamentous actin levels, increased globular actin accumulation, and impaired the nuclear translocation of MRTFA. Furthermore, WAVE2 depletion in myoblasts inhibited the expression and transcriptional activity of SRF and suppressed cell proliferation in myoblasts. Consequently, WAVE2 knockdown suppressed myogenic regulatory factors (i.e., MyoD, MyoG, and SMYD1) expressions, thereby hindering the differentiation of myoblasts. Thus, this study suggests that WAVE2 is essential for myogenic differentiation of progenitor cells by modulating the mechanosensitive MRTFA-SRF axis.

Keywords:  MRTFA; SRF; WAVE2; differentiation; myogenesis; proliferation

DOI:  https://doi.org/10.3390/cells13010009
Free Radic Biol Med. 2024 Jan 08. pii: S0891-5849(24)00008-X. [Epub ahead of print]

Oxidative stress and metabolism meet epigenetic modulation in physical exercise.

José Luis García-Giménez, Irene Cánovas-Cervera, Federico V Pallardó.

  Physical exercise is established as an important factor of health and generally is recommended for its positive effects on several tissues, organs, and systems. These positive effects come from metabolic adaptations that also include oxidative eustress, in which physical activity increases ROS production and antioxidant mechanisms, although this depends on the intensity of the exercise. Muscle metabolism through mechanisms such as aerobic and anaerobic glycolysis, tricarboxylic acid cycle, and oxidative lipid metabolism can produce metabolites and co-factors which directly impact the epigenetic machinery. In this review, we clearly reinforce the evidence that exercise regulates several epigenetic mechanisms and explain how these mechanisms can be regulated by metabolic products and co-factors produced during exercise. In fact, recent evidence has demonstrated the importance of epigenetics in the gene expression changes implicated in metabolic adaptation after exercise. Importantly, intermediates of the metabolism generated by continuous, acute, moderate, or strenuous exercise control the activity of epigenetic enzymes, therefore turning on or turning off the gene expression of specific programs which can lead to physiological adaptations after exercise.

Keywords:  Epigenetics; Oxidative stress; Physical exercise; Redox homeostasis

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.01.008
Biophys Rev. 2023 Dec;15(6): 1903-1907

Biophysical reviews top five: voltage-dependent charge movement in nerve and muscle.

Angela F Dulhunty.

  The discovery of gating currents and asymmetric charge movement in the early 1970s represented a remarkable leap forward in our understanding of the biophysical basis of voltage-dependent events that underlie electrical signalling that is vital for nerve and muscle function. Gating currents and charge movement reflect a fundamental process in which charged amino acid residues in an ion channel protein move in response to a change in the membrane electrical field and therefore activate the specific voltage-dependent response of that protein. The detection of gating currents and asymmetric charge movement over the past 50 years has been pivotal in unraveling the multiple molecular and intra-molecular processes which lead to action potentials in excitable tissues and excitation-contraction (EC) coupling in skeletal muscle. The recording of gating currents and asymmetric charge movement remains an essential component of investigations into the basic molecular mechanisms of neuronal conduction and muscle contraction.

Keywords:  Charge movement; Dihydropyridine receptor; Excitable membranes; Excitation-contraction coupling; Gating current; Na+ current; Nerve; Skeletal muscle

DOI:  https://doi.org/10.1007/s12551-023-01165-3
Sci Rep. 2024 01 08. 14(1): 755

Dietary oleic acid intake increases the proportion of type 1 and 2X muscle fibers in mice.

Yusuke Komiya, Shugo Iseki, Masaru Ochiai, Yume Takahashi, Issei Yokoyama, Takahiro Suzuki, Ryuichi Tatsumi, Shoko Sawano, Wataru Mizunoya, Keizo Arihara.

Skeletal muscle is one of the largest metabolic tissues in mammals and is composed of four different types of muscle fibers (types 1, 2A, 2X, and 2B); however, type 2B is absent in humans. Given that slow-twitch fibers are superior to fast-twitch fibers in terms of oxidative metabolism and are rich in mitochondria, shift of muscle fiber types in direction towards slower fiber types improves metabolic disorders and endurance capacity. We previously had reported that oleic acid supplementation increases type 1 fiber formation in C2C12 myotubes; however, its function still remains unclear. This study aimed to determine the effect of oleic acid on the muscle fiber types and endurance capacity. An in vivo mouse model was used, and mice were fed a 10% oleic acid diet for 4 weeks. Two different skeletal muscles, slow soleus muscle with the predominance of slow-twitch fibers and fast extensor digitorum longus (EDL) muscle with the predominance of fast-twitch fibers, were used. We found that dietary oleic acid intake improved running endurance and altered fiber type composition of muscles, the proportion of type 1 and 2X fibers increased in the soleus muscle and type 2X increased in the EDL muscle. The fiber type shift in the EDL muscle was accompanied by an increased muscle TAG content. In addition, blood triacylglycerol (TAG) and non-esterified fatty acid levels decreased during exercise. These changes suggested that lipid utilization as an energy substrate was enhanced by oleic acid. Increased proliferator-activated receptor γ coactivator-1β protein levels were observed in the EDL muscle, which potentially enhanced the fiber type transitions towards type 2X and muscle TAG content. In conclusion, dietary oleic acid intake improved running endurance with the changes of muscle fiber type shares in mice. This study elucidated a novel functionality of oleic acid in skeletal muscle fiber types. Further studies are required to elucidate the underlying mechanisms. Our findings have the potential to contribute to the field of health and sports science through nutritional approaches, such as the development of supplements aimed at improving muscle function.

DOI: https://doi.org/10.1038/s41598-023-50464-y
Am J Physiol Cell Physiol. 2024 Jan 09.

The Therapeutic Potential of Ketones in Cardiometabolic Disease: Impact on Heart and Skeletal Muscle.

Shubham Soni, Seyed Amirhossein Tabatabaei Dakhili, John R Ussher, Jason R B Dyck.

  β-hydroxybutyrate (βOHB) is the major ketone in the body and it is recognized as a metabolic energy source and an important signaling molecule. While ketone oxidation is essential in the brain during prolonged fasting/starvation, other organs such as skeletal muscle and the heart also use ketones as metabolic substrates. Additionally, βOHB-mediated molecular signaling events occur in heart and skeletal muscle cells, and via metabolism and/or signaling, ketones may contribute to optimal skeletal muscle health and cardiac function. Of importance, when the use of ketones for ATP production and/or as signaling molecules becomes disturbed in the presence of underlying obesity, type 2 diabetes and/or cardiovascular diseases, these changes may contribute to cardiometabolic disease. As a result of these disturbances in cardiometabolic disease, multiple approaches have been used to elevate circulating ketones with the goal of improving either ketone metabolism or ketone-mediated signaling. These approaches have produced significant improvements in heart and skeletal muscle during cardiometabolic disease with a wide range of benefits that include improved metabolism, weight loss, better glycemic control, improved cardiac and vascular function, as well as reduced inflammation and oxidative stress. Herein, we present the evidence that indicates that ketone therapy could be used as an approach to help treat cardiometabolic diseases by targeting cardiac and skeletal muscle.

Keywords:  cardiovascular disease; diabetes; heart failure; ketone bodies; β-hydroxybutyrate

DOI:  https://doi.org/10.1152/ajpcell.00501.2023
bioRxiv. 2023 Dec 21. pii: 2023.12.20.572678. [Epub ahead of print]

Characterization of NEB mutations in patients reveals novel nemaline myopathy disease mechanisms and omecamtiv mecarbil force effects.

Esmat Karimi, Mila van der Borgh, Johan Lindqvist, Jochen Gohlke, Zaynab Hourani, Justin Kolb, Stacy Cossette, Michael W Lawlor, Coen Ottenheijm, Henk Granzier.

Nebulin, a critical protein of the skeletal muscle thin filament, plays important roles in physiological processes such as regulating thin filament length (TFL), cross-bridge cycling, and myofibril alignment. Mutations in the nebulin gene ( NEB ) cause NEB-based nemaline myopathy (NEM2), a genetically heterogeneous disorder characterized by hypotonia and muscle weakness, currently lacking therapies targeting the underlying pathological mechanisms. In this study, we examined a cohort of ten NEM2 patients, each with unique mutations, aiming to understand their impact on mRNA, protein, and functional levels. Results show that truncation mutations affect NEB mRNA stability and lead to nonsense-mediated decay of the mutated transcript. Moreover, a high incidence of cryptic splice site activation was found in patients with splicing mutations which is expected to disrupt the actin-binding sites of nebulin. Determination of protein levels revealed patients with relatively normal nebulin levels and others with markedly reduced nebulin. We observed a positive relation between the reduction in nebulin and a reduction in TFL, and a positive relation between the reduction in nebulin level and the reduction in tension (both maximal and submaximal tension). Interestingly, our study revealed a duplication mutation in nebulin that resulted in a larger nebulin protein and longer TFL. Additionally, we investigated the effect of Omecamtiv mecarbil (OM), a small-molecule activator of cardiac myosin, on force production of type I muscle fibers of NEM2 patients. OM treatment substantially increased submaximal tension across all NEM2 patients ranging from 87-318%, with the largest effects in patients with the lowest level of nebulin. In summary, this study indicates that post-transcriptional or post-translational mechanisms regulate nebulin expression. Moreover, we propose that the pathomechanism of NEM2 involves not only shortened but also elongated thin filaments, along with the disruption of actin-binding sites resulting from splicing mutations. Significantly, our findings highlight the potential of OM treatment to improve skeletal muscle function in NEM2 patients, especially those with large reductions in nebulin levels.

DOI: https://doi.org/10.1101/2023.12.20.572678
Int J Sports Med. 2024 Jan 10.

Innovations in the Assessment of Skeletal Muscle Health: A Glimpse into the Future.

Jonathan P Beausejour, Kevan S Knowles, Abigail T Wilson, L Colby Mangum, Ethan C Hill, William J Hanney, Adam J Wells, David H Fukuda, Jeffrey Stout, Matt S Stock.

Skeletal muscle is the largest organ system in the human body and plays critical roles in athletic performance, mobility, and disease pathogenesis. Despite growing recognition of its importance by major health organizations, significant knowledge gaps remain regarding skeletal muscle health and its crosstalk with nearly every physiological system. Relevant public health challenges like pain, injury, obesity, and sarcopenia underscore the need to accurately assess skeletal muscle health and function. Feasible, non-invasive techniques that reliably evaluate metrics including muscle pain, dynamic structure, contractility, circulatory function, body composition, and emerging biomarkers are imperative to unraveling the complexities of skeletal muscle. Our concise review highlights innovative or overlooked approaches for comprehensively assessing skeletal muscle in vivo. We summarize recent advances in leveraging dynamic ultrasound imaging, muscle echogenicity, tensiomyography, blood flow restriction protocols, molecular techniques, body composition, and pain assessments to gain novel insight into muscle physiology from cellular to whole-body perspectives. Continued development of precise, non-invasive tools to investigate skeletal muscle are critical in informing impactful discoveries in exercise and rehabilitation science.

DOI: https://doi.org/10.1055/a-2242-3226