bims-moremu 2022-10-23 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2022–10–23
33 papers selected by
Anna Vainshtein, Craft Science Inc.

miRNA mediated downregulation of cyclase-associated protein 1 (CAP1) is required for myoblast fusion.
Inducible deletion of Raptor and mTOR from adult skeletal muscle impairs muscle contractility and relaxation.
Pyruvate dehydrogenase kinase 4 promotes ubiquitin-proteasome system-dependent muscle atrophy.
Engineered skeletal muscle recapitulates human muscle development, regeneration and dystrophy.
Single muscle fibre contractile function with ageing.
Efficient Downregulation of Alk4 in Skeletal Muscle After Systemic Treatment with Conjugated siRNAs in a Mouse Model for Duchenne Muscular Dystrophy.
Pax7+ Satellite Cells in Human Skeletal Muscle After Exercise: A Systematic Review and Meta-analysis.
Skeletal muscle mitochondrial remodeling in heart failure: An update on mechanisms and therapeutic opportunities.
Impact of cancer cachexia on respiratory muscle function and the therapeutic potential of exercise.
Resistance exercise enhances long-term mTORC1 sensitivity to leucine.
Isometric skeletal muscle contractile properties in common strains of male laboratory mice.
Temporal analysis of skeletal muscle remodelling post hindlimb ischemia reveals intricate autophagy regulation.
Dlk1-Dio3 cluster miRNAs regulate mitochondrial functions in the dystrophic muscle in Duchenne muscular dystrophy.
Decrotonylation of AKT1 promotes AKT1 phosphorylation and activation during myogenic differentiation.
Mechanical Strain Drives Exosome Production, Function, and miRNA Cargo in C2C12 Muscle Progenitor Cells.
Lcn2 mediates adipocyte-muscle-tumor communication and hypothermia in pancreatic cancer cachexia.
UBR2 targets myosin heavy chain IIb and IIx for degradation: Molecular mechanism essential for cancer-induced muscle wasting.
The regenerative potential of Pax3/Pax7 on skeletal muscle injury.
Greater Phosphorylation of AMPK and Multiple AMPK Substrates in the Skeletal Muscle of 24 Month-old Calorie Restricted Compared to Ad Libitum Fed Male Rats.
The location of protein oxidation in dystrophic skeletal muscle from the mdx mouse model of Duchenne muscular dystrophy.
Elevated muscle mass accompanied by transcriptional and nuclear alterations several months following cessation of resistance-type training in rats.
A systematic review and meta-analysis demonstrating Klotho as an emerging exerkine.
The Role of Mitochondrial and Redox Alterations in the Skeletal Myopathy Associated with Chronic Kidney Disease.
Maternal rodent exposure to di-(2-ethylhexyl) phthalate decreases muscle mass in the offspring by increasing myostatin.
Single-cell analysis of skeletal muscle macrophages reveals age-associated functional subpopulations.
COX7A2L genetic variants determine cardiorespiratory fitness in mice and human.
Myostatin: A Skeletal Muscle Chalone.
Gene editing of Duchenne muscular dystrophy using biomineralization-based spCas9 variant nanoparticles.
Increasing plasma L-kynurenine impairs mitochondrial oxidative phosphorylation prior to the development of atrophy in murine skeletal muscle: A pilot study.
Insulin resistance promotes extracellular BCAA accumulation without altering LAT1 content, independent of prior BCAA treatment in a myotube model of skeletal muscle.
Recent advances in cell-based and cell-free therapeutic approaches for sarcopenia.
Muscle atrophy phenotype gene expression during spaceflight is linked to a metabolic crosstalk in both the liver and the muscle in mice.
Irisin at the crossroads of inter-organ communications: Challenge and implications.

Front Cell Dev Biol. 2022 ;10 899917

miRNA mediated downregulation of cyclase-associated protein 1 (CAP1) is required for myoblast fusion.

Anurag Kumar Singh, Amrita Rai, Anja Weber, Guido Posern.

  Myoblast fusion is essential for the formation, growth, and regeneration of skeletal muscle, but the molecular mechanisms that govern fusion and myofiber formation remain poorly understood. Past studies have shown an important role of the actin cytoskeleton and actin regulators in myoblast fusion. The Cyclase-Associated Proteins (CAP) 1 and 2 recently emerged as critical regulators of actin treadmilling in higher eukaryotes including mammals. Whilst the role of CAP2 in skeletal muscle development and function is well characterized, involvement of CAP1 in this process remains elusive. Here we report that CAP1, plays a critical role in cytoskeletal remodeling during myoblast fusion and formation of myotubes. Cap1 mRNA and protein are expressed in both murine C2C12 and human LHCN-M2 myoblasts, but their abundance decreases during myogenic differentiation. Perturbing the temporally controlled expression of CAP1 by overexpression or CRISPR-Cas9 mediated knockout impaired actin rearrangement, myoblast alignment, expression of profusion molecules, differentiation into multinucleated myotubes, and myosin heavy chain expression. Endogenous Cap1 expression is post-transcriptionally downregulated during differentiation by canonical myomiRs miR-1, miR-133, and miR-206, which have conserved binding sites at the 3' UTR of the Cap1 mRNA. Deletion of the endogenous 3' UTR by CRISPR-Cas9 in C2C12 cells phenocopies overexpression of CAP1 by inhibiting myotube formation. Our findings implicates Cap1 and its myomiR-mediated downregulation in the myoblast fusion process and the generation of skeletal muscle.

Keywords:  CAP1; CAP2; microRNA; muscle differentiation; myogenesis; myosin heavy chain; post-transcriptional regulation

DOI:  https://doi.org/10.3389/fcell.2022.899917
J Physiol. 2022 Oct 18.

Inducible deletion of Raptor and mTOR from adult skeletal muscle impairs muscle contractility and relaxation.

Martina Baraldo, Sabrina Zorzato, Achille Homère Tchampda Dondjang, Alessia Geremia, Leonardo Nogara, Ana Georgia Dumitras, Marta Canato, Lorenzo Marcucci, Hendrik Nolte, Bert Blaauw.

   KEY POINTS: Skeletal muscle wasting and weakness have been associated with different pathological conditions, including sarcopenia and muscular dystrophy, and is accompanied by altered mTOR signaling Mammalian Target of Rapamycin (mTOR) plays a crucial role in the maintenance of muscle mass and functionality We found that the loss of both mTOR and Raptor results in contractile abnormalities, with severe muscle weakness and delayed relaxation following tetanic stimulation These results are associated with alterations in the expression of genes involved in sarcomere organization and calcium handling, and with an impairment in calcium reuptake after contraction Taken together, these results reveal a mechanistic insight into the role of mTOR in muscle contractility ABSTRACT: Skeletal muscle weakness has been associated with different pathological conditions, including sarcopenia and muscular dystrophy, and is accompanied by altered mTOR signaling. Here we wanted to better elucidate the functional role of mTOR on muscle contractility. Most loss of function studies for mTOR signaling have used the drug rapamycin to inhibit some of the signaling downstream of mTOR. However, as rapamycin does not completely inhibit all mTOR signaling, we generated a double k.o. for mTOR and for the scaffold protein of mTORC1, Raptor, in skeletal muscle. We found that dk.o. mice results in a more severe phenotype compared to Raptor or mTOR deletion alone. Indeed, they display muscle weakness, increased fiber denervation, and a slower muscle relaxation following tetanic stimulation. This is accompanied by a shift towards slow-twitch fibers and changes in the expression levels of calcium-related genes, like Serca1 and Casq1. Indeed, dk.o. mice show a decrease in calcium decay kinetics after tetanus in vivo, suggestive of a reduced calcium reuptake. In addition, RNA sequencing analysis revealed that many downregulated genes are linked to sarcomere organization, like Tcap and Fhod3. These results suggest a key role for mTOR signaling in maintaining a proper fiber relaxation in skeletal muscle. Abstract figure legend This article is protected by copyright. All rights reserved.

Keywords:  Raptor; calcium; mTOR; muscle force; relaxation; skeletal muscle

DOI:  https://doi.org/10.1113/JP283686
J Cachexia Sarcopenia Muscle. 2022 Oct 19.

Pyruvate dehydrogenase kinase 4 promotes ubiquitin-proteasome system-dependent muscle atrophy.

Ibotombi Singh Sinam, Dipanjan Chanda, Themis Thoudam, Min-Ji Kim, Byung-Gyu Kim, Hyeon-Ji Kang, Jung Yi Lee, Seung-Hoon Baek, Shin-Yoon Kim, Bum Jin Shim, Dongryeol Ryu, Jae-Han Jeon, In-Kyu Lee.

   BACKGROUND: Muscle atrophy, leading to muscular dysfunction and weakness, is an adverse outcome of sustained period of glucocorticoids usage. However, the molecular mechanism underlying this detrimental condition is currently unclear. Pyruvate dehydrogenase kinase 4 (PDK4), a central regulator of cellular energy metabolism, is highly expressed in skeletal muscle and has been implicated in the pathogenesis of several diseases. The current study was designed to investigated and delineate the role of PDK4 in the context of muscle atrophy, which could be identified as a potential therapeutic avenue to protect against dexamethasone-induced muscle wasting.
METHODS: The dexamethasone-induced muscle atrophy in C2C12 myotubes was evaluated at the molecular level by expression of key genes and proteins involved in myogenesis, using immunoblotting and qPCR analyses. Muscle dysfunction was studied in vivo in wild-type and PDK4 knockout mice treated with dexamethasone (25 mg/kg body weight, i.p., 10 days). Body weight, grip strength, muscle weight and muscle histology were assessed. The expression of myogenesis markers were analysed using qPCR, immunoblotting and immunoprecipitation. The study was extended to in vitro human skeletal muscle atrophy analysis.
RESULTS: Knockdown of PDK4 was found to prevent glucocorticoid-induced muscle atrophy and dysfunction in C2C12 myotubes, which was indicated by induction of myogenin (0.3271 ± 0.102 vs 2.163 ± 0.192, ****P < 0.0001) and myosin heavy chain (0.3901 ± 0.047 vs. 0.7222 ± 0.082, **P < 0.01) protein levels and reduction of muscle atrophy F-box (10.77 ± 2.674 vs. 1.518 ± 0.172, **P < 0.01) expression. In dexamethasone-induced muscle atrophy model, mice with genetic ablation of PDK4 revealed increased muscle strength (162.1 ± 22.75 vs. 200.1 ± 37.09 g, ***P < 0.001) and muscle fibres (54.20 ± 11.85% vs. 84.07 ± 28.41%, ****P < 0.0001). To explore the mechanism, we performed coimmunoprecipitation and liquid chromatography-mass spectrometry analysis and found that myogenin is novel substrate of PDK4. PDK4 phosphorylates myogenin at S43/T57 amino acid residues, which facilitates the recruitment of muscle atrophy F-box to myogenin and leads to its subsequent ubiquitination and degradation. Finally, overexpression of non-phosphorylatable myogenin mutant using intramuscular injection prevented dexamethasone-induced muscle atrophy and preserved muscle fibres.
CONCLUSIONS: We have demonstrated that PDK4 mediates dexamethasone-induced skeletal muscle atrophy. Mechanistically, PDK4 phosphorylates and degrades myogenin via recruitment of E3 ubiquitin ligase, muscle atrophy F-box. Rescue of muscle regeneration by genetic ablation of PDK4 or overexpression of non-phosphorylatable myogenin mutant indicates PDK4 as an amenable therapeutic target in muscle atrophy.

Keywords:  PDK4; glucocorticoids; muscle atrophy; myogenin; phosphorylation; ubiquitin-proteasomal system

DOI:  https://doi.org/10.1002/jcsm.13100
J Cachexia Sarcopenia Muscle. 2022 Oct 18.

Engineered skeletal muscle recapitulates human muscle development, regeneration and dystrophy.

Mina Shahriyari, Md Rezaul Islam, Sadman M Sakib, Malte Rinn, Anastasia Rika, Dennis Krüger, Lalit Kaurani, Verena Gisa, Mandy Winterhoff, Harithaa Anandakumar, Orr Shomroni, Matthias Schmidt, Gabriela Salinas, Andreas Unger, Wolfgang A Linke, Jana Zschüntzsch, Jens Schmidt, Rhonda Bassel-Duby, Eric N Olson, André Fischer, Wolfram-Hubertus Zimmermann, Malte Tiburcy.

   BACKGROUND: Human pluripotent stem cell-derived muscle models show great potential for translational research. Here, we describe developmentally inspired methods for the derivation of skeletal muscle cells and their utility in skeletal muscle tissue engineering with the aim to model skeletal muscle regeneration and dystrophy in vitro.
METHODS: Key steps include the directed differentiation of human pluripotent stem cells to embryonic muscle progenitors followed by primary and secondary foetal myogenesis into three-dimensional muscle. To simulate Duchenne muscular dystrophy (DMD), a patient-specific induced pluripotent stem cell line was compared to a CRISPR/Cas9-edited isogenic control line.
RESULTS: The established skeletal muscle differentiation protocol robustly and faithfully recapitulates critical steps of embryonic myogenesis in two-dimensional and three-dimensional cultures, resulting in functional human skeletal muscle organoids (SMOs) and engineered skeletal muscles (ESMs) with a regeneration-competent satellite-like cell pool. Tissue-engineered muscle exhibits organotypic maturation and function (up to 5.7 ± 0.5 mN tetanic twitch tension at 100 Hz in ESM). Contractile performance could be further enhanced by timed thyroid hormone treatment, increasing the speed of contraction (time to peak contraction) as well as relaxation (time to 50% relaxation) of single twitches from 107 ± 2 to 75 ± 4 ms (P < 0.05) and from 146 ± 6 to 100 ± 6 ms (P < 0.05), respectively. Satellite-like cells could be documented as largely quiescent PAX7+ cells (75 ± 6% Ki67- ) located adjacent to muscle fibres confined under a laminin-containing basal membrane. Activation of the engineered satellite-like cell niche was documented in a cardiotoxin injury model with marked recovery of contractility to 57 ± 8% of the pre-injury force 21 days post-injury (P < 0.05 compared to Day 2 post-injury), which was completely blocked by preceding irradiation. Absence of dystrophin in DMD ESM caused a marked reduction of contractile force (-35 ± 7%, P < 0.05) and impaired expression of fast myosin isoforms resulting in prolonged contraction (175 ± 14 ms, P < 0.05 vs. gene-edited control) and relaxation (238 ± 22 ms, P < 0.05 vs. gene-edited control) times. Restoration of dystrophin levels by gene editing rescued the DMD phenotype in ESM.
CONCLUSIONS: We introduce human muscle models with canonical properties of bona fide skeletal muscle in vivo to study muscle development, maturation, disease and repair.

Keywords:  Duchenne muscular dystrophy; hypaxial dermomyotome; limb muscle; satellite cells; skeletal muscle organoid; somite; tissue engineering

DOI:  https://doi.org/10.1002/jcsm.13094
J Physiol. 2022 Oct 21.

Single muscle fibre contractile function with ageing.

Gregory J Grosicki, Carlos S Zepeda, Christopher W Sundberg.

  Ageing is accompanied by decrements in the size and function of skeletal muscle that compromises independence and quality of life in older adults. Developing therapeutic strategies to ameliorate these changes is critical but requires an in-depth mechanistic understanding of the underlying physiology. Over the past 25 years, studies on the contractile mechanics of isolated human muscle fibres have been instrumental in facilitating our understanding of the cellular mechanisms contributing to age-related skeletal muscle dysfunction. The purpose of this review is to characterize the changes that occur in single muscle fibre size and contractile function with ageing and identify key areas for future research. Surprisingly, most studies observe that the size and contractile function of fibres expressing slow myosin heavy chain (MHC) I are well-preserved with ageing. In contrast, there are profound age-related decrements in the size and contractile function of the fibres expressing the MHC II isoforms. Notably, lifelong aerobic exercise training is unable to prevent most of the decrements in fast fibre contractile function, which have been implicated as a primary mechanism for the age-related loss in whole-muscle power output. These findings reveal a critical need to investigate the effectiveness of other nutritional, pharmaceutical, or exercise strategies, such as lifelong resistance training, to preserve fast fibre size and function with ageing. Moreover, integrating single fibre contractile mechanics with the molecular profile and other parameters important to contractile function (e.g., phosphorylation of regulatory proteins, innervation status, mitochondrial function, fibre economy) is necessary to comprehensively understand the ageing skeletal muscle phenotype. Abstract figure legend Advancing age is accompanied by decrements in whole-muscle strength and power that exceed the losses in muscle mass. The single fibre preparation has been instrumental in facilitating our understanding of the cellular mechanisms contributing to this phenomenon. Surprisingly, and at odds with some of the earlier findings, both size and contractile function (force, power, shortening velocity, Ca2+ sensitivity, and rates of force development [RFD]) of the MHC I fibres appear well-preserved with ageing. In contrast, several studies observe profound age-related decrements in function - namely force and power - of the MHC II fibres. The decrements in MHC II fibre function are primarily attributable to fibre atrophy, rather than age-related alterations in the intrinsic contractile mechanics, per se. Since MHC II fibres can generate greater force and power than MHC I fibres, these findings implicate fast fibre atrophy as an important therapeutic target for attenuating age-related decrements in whole-muscle strength and power. This article is protected by copyright. All rights reserved.

Keywords:  cross-bridge cycle; muscle power; muscle quality; myosin heavy chain; older adult; shortening velocity; skeletal muscle

DOI:  https://doi.org/10.1113/JP282298
Nucleic Acid Ther. 2022 Oct 20.

Efficient Downregulation of Alk4 in Skeletal Muscle After Systemic Treatment with Conjugated siRNAs in a Mouse Model for Duchenne Muscular Dystrophy.

Sarah Engelbeen, Svetlana Pasteuning-Vuhman, Joke Boertje-van der Meulen, Rubina Parmar, Klaus Charisse, Laura Sepp-Lorenzino, Muthiah Manoharan, Annemieke Aartsma-Rus, Maaike van Putten.

  Downregulation of genes involved in the secondary pathology of Duchenne muscular dystrophy, for example, inflammation, fibrosis, and adiposis, is an interesting approach to ameliorate degeneration of muscle and replacement by fibrotic and adiposis tissue. Small interfering RNAs (siRNAs) are able to downregulate target genes, however, delivery of siRNAs to skeletal muscle still remains a challenge. We investigated delivery of fully chemically modified, cholesterol-conjugated siRNAs targeting Alk4, a nontherapeutic target that is expressed highly in muscle. We observed that a single intravenous or intraperitoneal (IP) injection of 10 mg/kg resulted in significant downregulation of Alk4 mRNA expression in skeletal muscles in both wild-type and mdx mice. Treatment with multiple IP injections of 10 mg/kg led to an overall reduction of Alk4 expression, reaching significance in tibialis anterior (39.7% ± 6.2%), diaphragm (32.7% ± 5.8%), and liver (41.3% ± 29.9%) in mdx mice. Doubling of the siRNA dose did not further increase mRNA silencing in muscles of mdx mice. The chemically modified conjugated siRNAs used in this study are very promising for delivery to both nondystrophic and dystrophic muscles and could have major implications for treatment of muscular dystrophy pathology.

Keywords:  delivery; dystrophin; mdx mouse; pathology

DOI:  https://doi.org/10.1089/nat.2022.0021
Sports Med. 2022 Oct 20.

Pax7+ Satellite Cells in Human Skeletal Muscle After Exercise: A Systematic Review and Meta-analysis.

Luthfia Dewi, Yin-Chou Lin, Andrew Nicholls, Giancarlo Condello, Chih-Yang Huang, Chia-Hua Kuo.

BACKGROUND: Skeletal muscle has extraordinary regenerative capabilities against challenge, mainly owing to its resident muscle stem cells, commonly identified by Pax7+, which expediently donate nuclei to the regenerating multinucleated myofibers. This local reserve of stem cells in damaged muscle tissues is replenished by undifferentiated bone marrow stem cells (CD34+) permeating into the surrounding vascular system.
OBJECTIVE: The purpose of the study was to provide a quantitative estimate for the changes in Pax7+ muscle stem cells (satellite cells) in humans following an acute bout of exercise until 96 h, in temporal relation to circulating CD34+ bone marrow stem cells. A subgroup analysis of age was also performed.
METHODS: Four databases (Web of Science, PubMed, Scopus, and BASE) were used for the literature search until February 2022. Pax7+ cells in human skeletal muscle were the primary outcome. Circulating CD34+ cells were the secondary outcome. The standardized mean difference (SMD) was calculated using a random-effects meta-analysis. Subgroup analyses were conducted to examine the influence of age, training status, type of exercise, and follow-up time after exercise.
RESULTS: The final search identified 20 studies for Pax7+ cells comprising a total of 370 participants between the average age of 21 and 74 years and 26 studies for circulating CD34+ bone marrow stem cells comprising 494 participants between the average age of 21 and 67 years. Only one study assessed Pax7+ cells immediately after aerobic exercise and showed a 32% reduction in exercising muscle followed by a fast repletion to pre-exercise level within 3 h. A large effect on increasing Pax7+ cell content in skeletal muscles was observed 24 h after resistance exercise (SMD = 0.89, p < 0.001). Pax7+ cells increased to ~ 50% above pre-exercise level 24-72 h after resistance exercise. For a subgroup analysis of age, a large effect (SMD = 0.81, p < 0.001) was observed on increasing Pax7+ cells in exercised muscle among adults aged > 50 years, whereas adults at younger age presented a medium effect (SMD = 0.64, p < 0.001). Both resistance exercise and aerobic exercise showed a medium overall effect in increasing circulating CD34+ cells (SMD = 0.53, p < 0.001), which declined quickly to the pre-exercise baseline level after exercise within 6 h.
CONCLUSIONS: An immediate depletion of Pax7+ cells in exercising skeletal muscle concurrent with a transient release of CD34+ cells suggest a replenishment of the local stem cell reserve from bone marrow. A protracted Pax7+ cell expansion in the muscle can be observed during 24-72 h after resistance exercise. This result provides a scientific basis for exercise recommendations on weekly cycles allowing for adequate recovery time. Exercise-induced Pax7+ cell expansion in muscle remains significant at higher age, despite a lower stem cell reserve after age 50 years. More studies are required to confirm whether Pax7+ cell increment can occur after aerobic exercise.
CLINICAL TRIAL REGISTRATION: Registered at the International Prospective Register of Systematic Reviews (PROSPERO) [identification code CRD42021265457].

DOI: https://doi.org/10.1007/s40279-022-01767-z
Biomed Pharmacother. 2022 Nov;pii: S0753-3322(22)01222-7. [Epub ahead of print]155 113833

Skeletal muscle mitochondrial remodeling in heart failure: An update on mechanisms and therapeutic opportunities.

Jiayu Lv, Yumeng Li, Shuqing Shi, Xia Xu, Huaqin Wu, Bingxuan Zhang, Qingqiao Song.

  Patients with heart failure (HF) usually present with skeletal muscle diseases of varying severity, ranging from early fatigue on exercise to sarcopenia, sarcopenic obesity or cachexia, and frailty, which are significant predictors of HF prognosis. Abnormal mitochondrial metabolism has been identified as one of the earliest signs of skeletal muscle injury in HF and is associated with pathological alterations in muscle, manifested as muscle wasting, myocyte atrophy and apoptosis, fiber type shift, impaired contractile coupling, and muscle fat infiltration. In this review, we update the evidence for skeletal muscle mitochondrial remodeling in HF patients or animal models, including the impairments in mitochondrial ultrastructure, oxidative metabolism, electron transport chain (ETC), phosphorylation apparatus, phosphotransfer system, and quality control. We also focus on molecular regulatory mechanisms upstream of mitochondria, including circulating factors (e.g., RAAS, TNF-α IL-6, IGF-1, GH, ghrelin, adiponectin, NO) and molecular signals within myocytes (e.g., PGC-1α, PPARs, AMPK, SIRT1/3, ROS, and MuRF1). Besides the therapies targeting the signaling pathways mentioned above, such as AdipoRon and elamipretide, we further summarize other potential pharmacological approaches like inhibitors of sodium-glucose cotransporter 2 (SGLT2) and dipeptidyl peptidase-4 (DPP-4), as well as some natural products, which may have the beneficial effects on improving the skeletal muscle mitochondrial function of HF. Targeting myocyte mitochondrial biogenesis, oxidative metabolism, oxidative phosphorylation, and reduction of oxidative stress injury are promising future opportunities for the prevention and management of skeletal muscle myopathy in HF.

Keywords:  Heart failure; Mitochondria; Molecular mechanisms; Pharmacological targets; Skeletal muscle

DOI:  https://doi.org/10.1016/j.biopha.2022.113833
J Physiol. 2022 Oct 17.

Impact of cancer cachexia on respiratory muscle function and the therapeutic potential of exercise.

Ben T Murphy, John J Mackrill, Ken D O'Halloran.

  Cancer cachexia is defined as a multi-factorial syndrome characterised by an ongoing loss of skeletal muscle mass and progressive functional impairment, estimated to affect 50-80% of patients and responsible for 20% of cancer deaths. Elevations in the morbidity and mortality rates of cachectic cancer patients has been linked to respiratory failure due to atrophy and dysfunction of the ventilatory muscles. Despite this, there is a distinct scarcity of research investigating the structural and functional condition of the respiratory musculature in cancer, with the majority of studies exclusively focussing on limb muscle. Treatment strategies are largely ineffective in mitigating the cachectic state. It is now widely accepted that an efficacious intervention will likely combine elements of pharmacology, nutrition, and exercise. However, of these approaches, exercise has received comparatively little attention. Therefore, it is unlikely to be implemented optimally, whether in isolation or combination. In consideration of these limitations, the current review describes the mechanistic basis of cancer cachexia, and subsequently explores the available respiratory- and exercise-focussed literature within this context. The molecular basis of cachexia is thoroughly reviewed. The pivotal role of inflammatory mediators is described. Unravelling the mechanisms of exercise-induced support of muscle via antioxidant and anti-inflammatory effects in addition to promoting efficient energy metabolism via increased mitochondrial biogenesis, mitochondrial function, and muscle glucose uptake provide avenues for interventional studies. Currently available pre-clinical mouse models including novel transgenic animals provide a platform for the development of multi-modal therapeutic strategies to protect respiratory muscles in people with cancer. Abstract figure legend Cancer cachexia is characterised by profound loss of skeletal muscle mass. Exercise has the potential to counteract several factors that contribute to muscle wasting. Atrophy and dysfunction of the ventilatory muscles can result in respiratory compromise and ultimately failure. There is a scarcity of research investigating structure and function of the respiratory musculature in cancer. Pre-clinical and clinical studies focussed on mechanisms of exercise-induced support of muscle are required to drive the development of multi-modal therapeutic strategies to protect respiratory muscles in people with cancer. This article is protected by copyright. All rights reserved.

Keywords:  cachexia; cancer; exercise; respiratory system

DOI:  https://doi.org/10.1113/JP283569
Mol Metab. 2022 Oct 14. pii: S2212-8778(22)00184-3. [Epub ahead of print] 101615

Resistance exercise enhances long-term mTORC1 sensitivity to leucine.

Gommaar D'Hulst, Evi Masschelein, Katrien De Bock.

   OBJECTIVE: Exercise enhances the sensitivity of mammalian target of rapamycin complex 1 (mTORC1) to amino acids, in particular leucine. How long this enhanced sensitivity lasts, and which mechanisms control enhanced leucine-mediated mTORC1 activation following exercise is currently unknown.
METHODS: C57BL/6J mice were exercised for one night in a resistance-braked running wheel after a 12-day acclimatization period. Mice were gavaged with a submaximal dose of L-leucine or saline acutely or 48 hours after exercise cessation, following 3 h food withdrawal. Muscles were excised 30 min after leucine administration. To study the contribution of mTORC1, we repeated those experiments but blocked mTORC1 activation using rapamycin immediately before the overnight running bout and one hour before the first dose of leucine. mTORC1 signaling, muscle protein synthesis and amino acid sensing machinery were assessed using immunoblot and qPCR. Leucine uptake was measured using L-[14C(U)]-leucine tracer labeling.
RESULTS: When compared to sedentary conditions, leucine supplementation more potently activated mTORC1 and protein synthesis in acutely exercised muscle. This effect was observed in m. soleus but not in m. tibialis anterior nor m. plantaris. The synergistic effect in m. soleus was long-lasting as key downstream markers of mTORC1 as well as protein synthesis remained higher when leucine was administered 48 h after exercise. We found that exercise enhanced the expression of amino acid transporters and promoted uptake of leucine into the muscle, leading to higher free intramuscular leucine levels. This coincided with increased expression of activating transcription factor 4 (ATF4), a main transcriptional regulator of amino acid uptake and metabolism, and downstream activation of amino acid genes as well as leucyl-tRNA synthetase (LARS), a putative leucine sensor. Finally, blocking mTORC1 using rapamycin did not reduce expression and activation of ATF4, suggesting that the latter does not act downstream of mTORC1. Rather, we found a robust increase in eukaryotic initiation factor 2α (eIF2α) phosphorylation, suggesting that the integrated stress response pathway, rather than exercise-induced mTORC1 activation, drives long-term ATF4 expression in skeletal muscle after exercise.
CONCLUSIONS: The enhanced sensitivity of mTORC1 to leucine is maintained at least 48 h after exercise. This shows that the anabolic window of opportunity for protein ingestion is not restricted to the first hours immediately following exercise. Increased mTORC1 sensitivity to leucine coincided with enhanced leucine influx into muscle and higher expression of genes involved in leucine sensing and amino acid metabolism. Also, exercise induced an increase in ATF4 protein expression. Altogether, these data suggest that muscular contractions switch on a coordinated program to enhance amino acid uptake as well as intramuscular sensing of key amino acids involved in mTORC1 activation and the stimulation of muscle protein synthesis.

Keywords:  ATF4; exercise; leucine; mTOR; sensitivity

DOI:  https://doi.org/10.1016/j.molmet.2022.101615
Front Physiol. 2022 ;13 937132

Isometric skeletal muscle contractile properties in common strains of male laboratory mice.

Everett C Minchew, Nicholas C Williamson, Andrew T Readyoff, Joseph M McClung, Espen E Spangenburg.

  Assessing contractile function of skeletal muscle in murine models is a commonly employed laboratory technique that investigators utilize to measure the impact of genetic manipulations, drug efficacy, or other therapeutic interventions. Often overlooked is the potential for the strain of the mouse to influence the functional properties of the skeletal muscle. Thus, we sought to characterize commonly assessed isometric force measures in the hindlimb muscles across a variety of mouse strains. Using 6-8-week-old male mice, we measured isometric force, fatigue susceptibility, relaxation kinetics, muscle mass, myofiber cross-sectional area, and fiber type composition of the extensor digitorum longus (EDL) and soleus muscles in C57BL/6NJ, BALB/cJ, FVB/NJ, C57BL/6J, and C57BL/10 mice. The data demonstrate both unique differences and a number of similarities between both muscles in the various genetic backgrounds of mice. Soleus muscle specific force (i.e., force per unit size) exhibited higher variation across strains while specific force of the EDL muscle exhibited minimal variation. In contrast, absolute force differed only in a few mouse strains whereas analysis of muscle morphology revealed many distinctions when compared across all the groups. Collectively, the data suggest that the strain of the mouse can potentially influence the measured biological outcome and may possibly promote a synergistic effect with any genetic manipulation or therapeutic intervention. Thus, it is critical for the investigator to carefully consider the genetic background of the mouse used in the experimental design and precisely document the strain of mouse employed during publication.

Keywords:  force; genetics; mouse model; muscle mass; skeletal muscle

DOI:  https://doi.org/10.3389/fphys.2022.937132
Am J Physiol Cell Physiol. 2022 Oct 17.

Temporal analysis of skeletal muscle remodelling post hindlimb ischemia reveals intricate autophagy regulation.

Mattia Scalabrin, Viktor Engman, Amanda Maccannell, Annabel Critchlow, Lee D Roberts, Nadira Yudalsheva, T Scott Bowen.

  Hind Limb Ischemia (HLI) is the most severe form of peripheral arterial disease, associated with a substantial reduction of limb blood flow that impairs skeletal muscle homeostasis to promote functional disability. The molecular regulators of HLI-induced muscle perturbations remain poorly defined. This study investigated whether perturbations in the molecular catabolic-autophagy signalling network were linked to temporal remodelling of skeletal muscle in HLI. HLI was induced via hindlimb ischemia (femoral artery ligation) and confirmed by Doppler echocardiography. Experiments were terminated at time points defined as early- (7 days; n=5) or late (28 days; n=5) stage HLI. Ischemic and non-ischemic (contralateral) limb muscles were compared. Ischemic vs. non-ischemic muscles demonstrated overt remodelling at early-HLI but normalised at late-HLI. Early-onset fibre atrophy was associated with excessive autophagy signalling in ischemic muscle: protein expression increased for Beclin-1, LC3 and p62 (p<0.05) but proteasome-dependent markers were reduced (p<0.05). Mitophagy signalling increased in early-stage HLI which aligned with an early and sustained loss of mitochondrial content (p<0.05). Upstream autophagy regulators Sestrins showed divergent responses during early-stage HLI (Sestrin2 increased while Sestrin1 decreased; p<0.05) in parallel to increased AMPK phosphorylation (p<0.05) and lower antioxidant enzyme expression. No changes were found in markers for mTORC1 signalling. These data indicate early-activation of the sestrin-AMPK signalling axis may regulate autophagy to stimulate rapid and overt muscle atrophy in HLI, which is normalised within weeks and accompanied by recovery of muscle mass. A complex interplay between Sestrins to regulate autophagy signalling during early-to-late muscle remodelling in HLI is likely.

Keywords:  Autophagy; Ischemia; Sestrins; Skeletal Muscle

DOI:  https://doi.org/10.1152/ajpcell.00174.2022
Life Sci Alliance. 2023 Jan;pii: e202201506. [Epub ahead of print]6(1):

Dlk1-Dio3 cluster miRNAs regulate mitochondrial functions in the dystrophic muscle in Duchenne muscular dystrophy.

Ai Vu Hong, Nathalie Bourg, Peggy Sanatine, Jerome Poupiot, Karine Charton, Evelyne Gicquel, Emmanuelle Massourides, Marco Spinazzi, Isabelle Richard, David Israeli.

Duchenne muscular dystrophy (DMD) is a severe muscle disease caused by impaired expression of dystrophin. Whereas mitochondrial dysfunction is thought to play an important role in DMD, the mechanism of this dysfunction remains to be clarified. Here we demonstrate that in DMD and other muscular dystrophies, a large number of Dlk1-Dio3 clustered miRNAs (DD-miRNAs) are coordinately up-regulated in regenerating myofibers and in the serum. To characterize the biological effect of this dysregulation, 14 DD-miRNAs were simultaneously overexpressed in vivo in mouse muscle. Transcriptomic analysis revealed highly similar changes between the muscle ectopically overexpressing 14 DD-miRNAs and the mdx diaphragm, with naturally up-regulated DD-miRNAs. Among the commonly dysregulated pathway we found repressed mitochondrial metabolism, and oxidative phosphorylation (OxPhos) in particular. Knocking down the DD-miRNAs in iPS-derived skeletal myotubes resulted in increased OxPhos activities. The data suggest that (1) DD-miRNAs are important mediators of dystrophic changes in DMD muscle, (2) mitochondrial metabolism and OxPhos in particular are targeted in DMD by coordinately up-regulated DD-miRNAs. These findings provide insight into the mechanism of mitochondrial dysfunction in muscular dystrophy.

DOI: https://doi.org/10.26508/lsa.202201506
J Adv Res. 2022 Oct 17. pii: S2090-1232(22)00235-1. [Epub ahead of print]

Decrotonylation of AKT1 promotes AKT1 phosphorylation and activation during myogenic differentiation.

Zhengyu Qian, Jingwei Ye, Jinteng Li, Yunshu Che, Wenhui Yu, Peitao Xu, Jiajie Lin, Feng Ye, Xiaojun Xu, Zepeng Su, Dateng Li, Zhongyu Xie, Yanfeng Wu, Huiyong Shen.

   INTRODUCTION: Myogenic differentiation plays an important role in pathophysiological processes including muscle injury and regeneration, as well as muscle atrophy. A novel type of posttranslational modification, crotonylation, has been reported to play a role in stem cell differentiation and disease. However, the role of crotonylation in myogenic differentiation has not been clarified.
OBJECTIVES: This study aims to find the role of crotonylation during myogenic differentiation and explore whether it is a potential target in myogenic dysfunction disease.
METHODS: C2C12 cell line and skeletal muscle mesenchymal progenitors of Mus musculus were used for myogenic process study in vitro, while muscle injury model of mice was used for in vivo muscle regeneration study. Mass spectrometry favored in discovery of potential target protein of crotonylation and its specific sites.
RESULTS: We confirmed the gradual decrease in total protein crotonylation level during muscle differentiation and found decreased crotonylation of AKT1, which facilitated an increase in AKT1 phosphorylation. Then we verified that crotonylation of AKT1 at specific sites weakened its binding with PDK1 and impaired its phosphorylation. In addition, we found that increased expression of the crotonylation eraser HDAC3 decreased AKT1 crotonylation levels during myogenic differentiation, jointly promoting myogenic differentiation.
CONCLUSION: Our study highlights the important role of decrotonylation of AKT1 in the process of muscle differentiation, where it aids the phosphorylation and activation of AKT1 and promotes myogenic differentiation. This is of great significance for exploring the pathophysiological process of muscle injury repair and sarcopenia.

Keywords:  AKT1; Crotonylation; Myogenic differentiation; Phosphorylation

DOI:  https://doi.org/10.1016/j.jare.2022.10.005
J Orthop Res. 2022 Oct 17.

Mechanical Strain Drives Exosome Production, Function, and miRNA Cargo in C2C12 Muscle Progenitor Cells.

Michael Mullen, Katherine Williams, Tom LaRocca, Victoria Duke, William Sealy Hambright, Sudheer Ravuri, Chelsea Bahney, Nicole Ehrhart, Johnny Huard.

  Mesenchymal stem cells (MSCs) have been proven to promote tissue repair. However, concerns related to their clinical application and regulatory hurdles remain. Recent data has demonstrated the pro-regenerative secretome of MSCs can result in similar effects in the absence of the cells themselves. Within the secretome, exosomes have emerged as a promising regenerative component. Exosomes, which are nanosized lipid vesicles secreted by cells, encapsulate miRNA, RNA, and proteins that drive MSCs regenerative potential with cell specific content. As such, there is an opportunity to optimize the regenerative potential of MSCs, and thus their secreted exosome fraction, to improve clinical efficacy. Exercise is one factor that has been shown to improve muscle progenitor cell function and regenerative potential. However, the effect of exercise on MSC exosome content and function is still unclear. To address this, we used an in vitro culture system to evaluate the effects of mechanical strain, an exercise mimetic, on C2C12 (muscle progenitor cell) exosome production and pro-regenerative function. Our results indicate that the total exosome production is increased by mechanical strain and can be regulated with different tensile loading regimens. Furthermore, we found that exosomes from mechanically stimulated cells increase proliferation and myogenic differentiation of naïve C2C12 cells. Lastly, we show that exosomal miRNA cargo is differentially expressed following strain. Gene ontology mapping suggests positive regulation of BMP signaling, regulation of actin-filament based processes, and muscle cell apoptosis may be at least partially responsible for the pro-regenerative effects of exosomes from mechanically stimulated C2C12 muscle progenitor cells. This article is protected by copyright. All rights reserved.

Keywords:  Exercise; Exosomes; Mechanical Strain; Muscle; miRNA

DOI:  https://doi.org/10.1002/jor.25467
Mol Metab. 2022 Oct 13. pii: S2212-8778(22)00181-8. [Epub ahead of print] 101612

Lcn2 mediates adipocyte-muscle-tumor communication and hypothermia in pancreatic cancer cachexia.

Mengistu Lemecha, Jaya Chalise, Yuki Takamuku, Guoxiang Zhang, Takahiro Yamakawa, Garrett Larson, Keiichi Itakura.

   OBJECTIVE: Adipose tissue is the largest endocrine organ. When activated by cancer cells, adipocytes secrete adipocytokines and release fatty acids, which are then transferred to cancer cells and used for structural and biochemical support. How this metabolic symbiosis between cancer cells and adipocytes affects skeletal muscle and thermogenesis during cancer cachexia is unknown. Cancer cachexia is a multiorgan syndrome and how the communication between tissues is established has yet to be determined. We investigated adipose tissue secretory factors and explored their role in crosstalk of adipocytes, muscle, and tumor during pancreatic cancer cachexia.
METHODS: We used a pancreatic cancer cachexia mouse model generated by syngenic implantation of pancreatic ductal adenocarcinoma (PDAC) cells (KPC) intraperitoneally into C57BL/6 mice and Lcn2-knockout mice. For in vitro studies, adipocytes (3T3-L1 and primary adipocytes), cachectic cancer cells (Panc0203), non-cachectic cancer cells (Du145 cells), and skeletal muscle cells (C2C12 myoblasts) were used.
RESULTS: To identify molecules involved in the crosstalk of adipose tissue with muscle and tumors, we treated 3T3-L1 adipocytes with conditioned medium (CM) from cancer cells. Upon screening the secretomes from PDAC-induced adipocytes, several adipocytokines were identified, including lipocalin 2 (Lcn2). We investigated Lcn2 as a potential mediator of cachexia induced by adipocytes in response to PDAC. During tumor progression, mice exhibited a decline in body weight gain, which was accompanied by loss of adipose and muscle tissues. Tumor-harboring mice developed drastic hypothermia because of a dramatic loss of fat in brown adipose tissue (BAT) and suppression of the thermogenesis pathway. We inhibited Lcn2 with an anti-Lcn2 antibody neutralization or genomic ablation in mice. Lcn2 deficiency significantly improved body temperature in tumor-bearing mice, which was supported by the increased expression of Ucp1 and β3-adrenergic receptor in BAT. In addition, Lcn2 inhibition abrogated the loss of fat and muscle in tumor-bearing mice. In contrast to tumor-bearing WT mice, the corresponding Lcn2-knockout mice showed reduced ATGL expression in iWAT and decreased the expression of muscle atrophy molecular markers MuRF-1 and Fbx32.
CONCLUSIONS: This study showed that Lcn2 is causally involved in the dysregulation of adipose tissue-muscle-tumor crosstalk during pancreatic cancer cachexia. Therapeutic targets that suppress Lcn2 may minimize the progression of cachexia.

Keywords:  BAT; Cachexia; Hypothermia; Lcn2; PDAC; Thermogenesis

DOI:  https://doi.org/10.1016/j.molmet.2022.101612
Proc Natl Acad Sci U S A. 2022 Oct 25. 119(43): e2200215119

UBR2 targets myosin heavy chain IIb and IIx for degradation: Molecular mechanism essential for cancer-induced muscle wasting.

Song Gao, Guohua Zhang, Zicheng Zhang, James Z Zhu, Li Li, Yong Zhou, George G Rodney, Reem S Abo-Zahrah, Lindsey Anderson, Jose M Garcia, Yong Tae Kwon, Yi-Ping Li.

  Cancer cachexia is a lethal metabolic syndrome featuring muscle wasting with preferential loss of fast-twitching muscle mass through an undefined mechanism. Here, we show that cancer induces muscle wasting by selectively degrading myosin heavy chain (MHC) subtypes IIb and IIx through E3 ligase UBR2-mediated ubiquitylation. Induction of MHC loss and atrophy in C2C12 myotubes and mouse tibialis anterior (TA) by murine cancer cells required UBR2 up-regulation by cancer. Genetic gain or loss of UBR2 function inversely altered MHC level and muscle mass in TA of tumor-free mice. UBR2 selectively interacted with and ubiquitylated MHC-IIb and MHC-IIx through its substrate recognition and catalytic domain, respectively, in C2C12 myotubes. Elevation of UBR2 in muscle of tumor-bearing or free mice caused loss of MHC-IIb and MHC-IIx but not MHC-I and MHC-IIa or other myofibrillar proteins, including α-actin, troponin, tropomyosin, and tropomodulin. Muscle-specific knockout of UBR2 spared KPC tumor-bearing mice from losing MHC-IIb and MHC-IIx, fast-twitching muscle mass, cross-sectional area, and contractile force. The rectus abdominis (RA) muscle of patients with cachexia-prone cancers displayed a selective reduction of MHC-IIx in correlation with higher UBR2 levels. These data suggest that UBR2 is a regulator of MHC-IIb/IIx essential for cancer-induced muscle wasting, and that therapeutic interventions can be designed by blocking UBR2 up-regulation by cancer.

Keywords:  MHC-IIb; MHC-IIx; UBR2; cancer cachexia; ubiquitylation

DOI:  https://doi.org/10.1073/pnas.2200215119
J Genet Eng Biotechnol. 2022 Oct 17. 20(1): 143

The regenerative potential of Pax3/Pax7 on skeletal muscle injury.

Muhamad Azhar, Bantari Wisynu Kusuma Wardhani, Editha Renesteen.

   BACKGROUND: Skeletal muscle mishaps are the most well-known incidents in society, especially among athletes and the military population. From the various urgency, this accident needs to be cured more quickly. However, the current treatment still has some shortcomings and is less effective. In this case, Paired box 3 and Paired box 7 (Pax3/Pax7) proteins that induce stem cells could potentially be an alternative treatment for skeletal muscle injuries. This paper aimed to analyse the potential treatment of Pax3/Pax7 proteins inducing the stem cell for skeletal muscle injuries. We did a narrative review by gathering several scientific journals from several leading platforms like PubMed and Scopus. As common accidents, skeletal muscle disease could be due to workplace and non-workplace causes. The highest risk occurs in the athlete and military environment. The treatment of current skeletal muscle injuries is protection, rest, ice, compression, and elevation (PRICE), non-steroidal anti-inflammatory drugs (NSAIDs), and mechanical stimulation. However, it is considered less effective, especially in NSAIDs, inhibiting myogenic cell proliferation. The current finding indicates that the stem cells have markers known as Pax3/Pax7. The role of both markers in muscle injury, Pax3/Pax7, as transcription factors will induce cell division by H3K4 methylation mechanisms and chromatin modifications that stimulate gene activation.
CONCLUSION: Regulation by Pax3/Pax7 factors that affect stem cells and stem cell proliferation is one of the alternative treatments. This regulation can accelerate the healing of injury victims, especially injuries to the skeletal muscles. Finally, after being compared, Pax3/Pax7 induces stem cells to have the potential to be one of the skeletal muscle injury treatments.

Keywords:  Athlete; Cell proliferation Injuries.; Pax3 and Pax7; Pax3/Pax7; Skeletal muscle; Stem cells

DOI:  https://doi.org/10.1186/s43141-022-00429-x
J Gerontol A Biol Sci Med Sci. 2022 Oct 21. pii: glac218. [Epub ahead of print]

Greater Phosphorylation of AMPK and Multiple AMPK Substrates in the Skeletal Muscle of 24 Month-old Calorie Restricted Compared to Ad Libitum Fed Male Rats.

Amy Zheng, Seong Eun Kwak, Jesper B Birk, Edward B Arias, Dominic Thorley, Jørgen F P Wojtaszewski, Gregory D Cartee.

  AMP-activated protein kinase (AMPK), a highly conserved, heterotrimeric serine/threonine kinase with critical sensory and regulatory functions, is proposed to induce anti-aging actions of caloric restriction (CR). Although earlier studies assessed CR's effects on AMPK in rodent skeletal muscle, the scope of these studies was narrow with limited focus on older animals. This study's purpose was to fill important knowledge gaps related to CR's influence on AMPK in skeletal muscle of older animals. Therefore, using epitrochlearis muscles from 24 month-old ad libitum fed (AL) and CR (consuming 65% of AL intake for 8 weeks), male Fischer-344 x Brown Norway F1 rats, we determined: 1) AMPK Thr172 phosphorylation (a key regulatory site) by immunoblot; 2) AMPKα1 and AMPKα2 activity (representing the two catalytic α-subunits of AMPK), and AMPKγ3 activity (representing AMPK complexes that include the skeletal muscle-selective regulatory γ3 subunit) using enzymatic assays; 3) phosphorylation of multiple protein substrates that are linked to CR-related effects (acetyl CoA carboxylase, ACC, that regulates lipid oxidation; Beclin-1 and ULK1 that are autophagy regulatory proteins; Raptor, mTORC1 complex protein that regulates autophagy; TBC1D1 and TBC1D4 that regulate glucose uptake) by immunoblot; and 4) ATP and AMP concentrations (key AMPK regulators) by mass spectrometry. The results revealed significant CR-associated increases in the phosphorylation of AMPK Thr172 and four AMPK substrates (ACC, Beclin-1, TBC1D1, TBC1D4), without significant diet-related differences in ATP or AMP concentration or AMPKα1-, AMPKα2-, or AMPKγ3-associated activity. The enhanced phosphorylation of multiple AMPK substrates provides novel mechanistic insights linking AMPK to functionally important consequences of CR.

Keywords:  Beclin-1; TBC1D1; TBC1D4; ULK1; acetyl-CoA carboxylase

DOI:  https://doi.org/10.1093/gerona/glac218
Acta Histochem. 2022 Oct 18. pii: S0065-1281(22)00118-0. [Epub ahead of print]124(8): 151959

The location of protein oxidation in dystrophic skeletal muscle from the mdx mouse model of Duchenne muscular dystrophy.

Tomohito Iwasaki, Jessica R Terrill, Kei Kawarai, Yusei Miyata, Takayoshi Tagami, Naoyuki Maeda, Yasuhiro Hasegawa, Takafumi Watanabe, Miranda D Grounds, Peter G Arthur.

  Duchenne muscular dystrophy (DMD) is a severe childhood disease characterised by progressive muscle wasting caused by widespread myofibre necrosis. Implicated in the pathology of DMD is oxidative stress, caused by excessive generation of reactive oxygen and nitrogen species (RONS). One consequence of RONS exposure is post-translational oxidative modifications to proteins, which can cause loss of protein function. This study used the dystrophic mdx mouse model for DMD to visualise the precise location of different oxidative modifications to proteins in dystrophic muscles, including both reversible (protein thiol oxidation and s-nitrosylation) and irreversible (carbonylation and dityrosine formation) oxidation at various stages of dystrophic muscle necrosis and regeneration. High levels of protein oxidation were observed in mdx myofibres undergoing degeneration and immune cell infiltration (myonecrosis). Since irreversible protein oxidation, especially dityrosine formation, was only colocalised to areas of myonecrosis, we suggest that this specific measurement could be a useful biomarker of myonecrosis. To test this we quantified dityrosines in muscle homogenates; this analysis showed significantly higher levels of dityrosines in mdx (compared with control normal) mice aged 23 days, an age when acute onset of extensive myonecrosis occurs in mdx muscles. These results indicate a major localised role of immune cells in RONS generation in dystrophic muscle, and strongly support a role for protein oxidation in myonecrosis and associated dystropathology. Consequently, the measurement of protein oxidation (specifically dityrosines) in dystrophic muscles may be a useful biomarker for indirectly quantifying myonecrosis in research studies using mdx mice and other animal models for DMD.

Keywords:  DMD; Dityrosines; Dystrophic muscle; Myonecrosis; Oxidised proteins; RONS; mdx mice

DOI:  https://doi.org/10.1016/j.acthis.2022.151959
Physiol Rep. 2022 Oct;10(20): e15476

Elevated muscle mass accompanied by transcriptional and nuclear alterations several months following cessation of resistance-type training in rats.

Erik P Rader, Brent A Baker.

  Rodent studies investigating long-term effects following termination of hypertrophy-inducing loading have predominantly involved exposures such as synergist ablation and weighted wheel running or ladder climbing. This research yielded a spectrum of results regarding the extent of detraining in terms of muscle mass and myonuclei number. The studies were also limited in their lack of sensitive performance measures and indirect relatedness to resistance training. Our research group developed and validated a relevant rat model of resistance-type training that induces increased muscle mass and performance. The aim of the present study was to determine to what extent these features persist 3 months following the termination of this training. While performance returned to baseline, muscle mass remained elevated by 17% and a shift in distribution to larger muscle fibers persisted. A 16% greater total RNA and heightened mRNA levels of ribosomal protein S6 kinases implicated preserved transcriptional output and ribosomal content. Remodeling of muscle fiber nuclei was consistent with these findings - increased nuclear number and a distribution shift to a more circular nuclear shape. These findings indicate that muscle mass detrains at a slower rate than performance and implicates multiple forms of myonuclear remodeling in muscle memory.

Keywords:  dorsiflexor muscles; dynamometer; skeletal muscle; stretch-shortening contractions

DOI:  https://doi.org/10.14814/phy2.15476
Sci Rep. 2022 Oct 20. 12(1): 17587

A systematic review and meta-analysis demonstrating Klotho as an emerging exerkine.

Hugo de Luca Corrêa, Artur Temizio Oppelt Raab, Thamires Marra Araújo, Lysleine Alves Deus, Andrea Lucena Reis, Fernando Sousa Honorato, Paolo Lucas Rodrigues-Silva, Rodrigo Vanerson Passos Neves, Henver Simionato Brunetta, Marcelo Alves da Silva Mori, Octávio Luiz Franco, Thiago Dos Santos Rosa.

Klotho is an anti-aging protein with several therapeutic roles in the pathophysiology of different organs, such as the skeletal muscle and kidneys. Available evidence suggests that exercise increases Klotho levels, regardless of the condition or intervention, shedding some light on this anti-aging protein as an emergent and promising exerkine. Development of a systematic review and meta-analysis in order to verify the role of different exercise training protocols on the levels of circulating soluble Klotho (S-Klotho) protein. A systematic search of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE through PubMed, EMBASE, CINAHL, CT.gov, and PEDro. Randomized and quasi-randomized controlled trials that investigated effects of exercise training on S-Klotho levels. We included 12 reports in the analysis, comprising 621 participants with age ranging from 30 to 65 years old. Klotho concentration increased significantly after chronic exercise training (minimum of 12 weeks) (Hedge' g [95%CI] 1.3 [0.69-1.90]; P < 0.0001). Moreover, exercise training increases S-Klotho values regardless of the health condition of the individual or the exercise intervention, with the exception of combined aerobic + resistance training. Furthermore, protocol duration and volume seem to influence S-Klotho concentration, since the effect of the meta-analysis changes when subgrouping these variables. Altogether, circulating S-Klotho protein is altered after chronic exercise training and it might be considered an exerkine. However, this effect may be influenced by different training configurations, including protocol duration, volume, and intensity.

DOI: https://doi.org/10.1038/s41598-022-22123-1
Antioxid Redox Signal. 2022 Oct 16.

The Role of Mitochondrial and Redox Alterations in the Skeletal Myopathy Associated with Chronic Kidney Disease.

Trace Thome, Kyoungrae Kim, Gengfu Dong, Terence E Ryan.

SIGNIFICANCE: An estimated 700 million people globally suffer from chronic kidney disease (CKD). In addition to increasing cardiovascular disease risk, CKD is a catabolic disease that results in loss of muscle mass and function which are strongly associated with mortality and reduced quality of life. Despite the importance of muscle health and function, there are no treatments available to prevent or attenuate the myopathy associated with CKD.
RECENT ADVANCES: Recent studies have begun to unravel the changes in mitochondrial and redox homeostasis within skeletal muscle during CKD. Impairments in mitochondrial metabolism, characterized by reduced oxidative phosphorylation, are found in both rodents and patients with CKD. Associated with aberrant mitochondrial function, clinical and preclinical findings have documented signs of oxidative stress, although the molecular source and species are ill-defined.
CRITICAL ISSUES: First, we review the pathobiology of CKD and its associated myopathy, and review muscle cell bioenergetics and redox biology. Second, we discuss evidence from clinical and preclinical studies that have implicated the involvement of mitochondrial and redox alterations in CKD-associated myopathy and review the underlying mechanisms reported. Third, discuss gaps in knowledge related to mitochondrial and redox alterations on muscle health and function in CKD.
FUTURE DIRECTIONS: Despite what has been learned, effective treatments to improve muscle health in CKD remain elusive. Further studies are needed to uncover the complex mitochondrial and redox alterations, including post-transcriptional protein alterations, in patients with CKD and how these changes interact with known or unknown catabolic pathways contributing to poor muscle health and function.

DOI: https://doi.org/10.1089/ars.2022.0143
J Cachexia Sarcopenia Muscle. 2022 Oct 19.

Maternal rodent exposure to di-(2-ethylhexyl) phthalate decreases muscle mass in the offspring by increasing myostatin.

Fengju Li, Ting Luo, Honghui Rong, Lu Lu, Ling Zhang, Chuanfeng Zheng, Dali Yi, Yi Peng, Enyu Lei, Xiaotao Xiong, Fengchao Wang, Jose M Garcia, Ji-An Chen.

   BACKGROUND: Di-(2-ethylhexyl) phthalate (DEHP) and its metabolites can cross the placenta and may cause birth defects and developmental disorders. However, whether maternal DEHP exposure affects skeletal muscle development in the offspring and the pathways involved are unknown. This study investigated the effects of maternal DEHP exposure and the contribution of myostatin (MSTN) to skeletal muscle development in the offspring.
METHODS: Pregnant wild-type and muscle-specific myostatin knockout (MSTN KO) C57BL/6 mice were randomized to receive vehicle (corn oil) or 250 mg/kg DEHP by gavage every other day until their pups were weaned (postnatal day 21 [PND21]). Body weights of the offspring mice were measured longitudinally, and their hindleg muscles were harvested at PD21. Also, C2C12 cells were treated with mono-2-ethylhexyl phthalate (MEHP), the primary metabolite of DEHP, and proteolysis, protein synthesis, and myogenesis markers were measured. The contribution of myostatin to maternal DEHP exposure-induced muscle wasting in the offspring was determined.
RESULTS: Maternal DEHP exposure reduced body weight growth, myofibre size, and muscle mass in the offspring compared to controls (Quad: 2.70 ± 0.1 vs. 3.38 ± 0.23, Gastroc: 2.29 ± 0.09 vs. 2.81 ± 0.14, Tibialis: 1.01 ± 0.07 vs. 1.25 ± 0.11, mg/tibial length in mm, all P < 0.01, n = 35). Maternal DEHP exposure significantly increased Myostatin expression (2.45 ± 0.41 vs. 0.03 ± 0.00 DEHP vs. controls, P < 0.01, n = 5), Atrogin-1(2.68 ± 0.65 vs. 0.63 ± 0.01, P < 0.05, n = 5), MuRF1 (1.56 ± 0.51 vs. 0.31 ± 0.01, P < 0.05, n = 5), and Smad2/3 phosphorylation (4.12 ± 0.35 vs. 0.49 ± 0.18, P < 0.05), and decreased MyoD (0.27 ± 0.01 vs. 1.52 ± 0.01, P < 0.05, n = 5), Myogenin (0.25 ± 0.03 vs. 1.95 ± 0.56, P < 0.05, n = 5), and AKT phosphorylation (4.12 ± 0.35 vs. 1.00 ± 0.06, P < 0.05, n = 5), in skeletal muscle of the offspring in MSTNflox/flox , but not in MSTN KO mice. Maternal DEHP exposure resulted in up-regulation of CCAAT/enhancer-binding protein δ (C/EBPδ, 4.12 ± 0.35 vs. 1.00 ± 0.19, P < 0.05, n = 5) in skeletal muscle of the offspring in MSTNflox/flox and MSTN KO mice (4.12 ± 0.35 vs. 4.35 ± 0.28, P > 0.05, n = 5). In vitro, C/EBPδ silencing abrogated the MEHP-induced increases in Myostatin, MuRF-1, and Atrogin-1 and decreases in MyoD and Myogenin expression.
CONCLUSIONS: Maternal DEHP exposure impairs skeletal muscle development in the offspring by enhancing the C/EBPδ-myostatin pathway in mice.

Keywords:  di-(2-ethylhexyl) phthalate; maternal; myostatin; offspring; skeletal muscle

DOI:  https://doi.org/10.1002/jcsm.13098
Elife. 2022 10 19. pii: e77974. [Epub ahead of print]11

Single-cell analysis of skeletal muscle macrophages reveals age-associated functional subpopulations.

Linda K Krasniewski, Papiya Chakraborty, Chang-Yi Cui, Krystyna Mazan-Mamczarz, Christopher Dunn, Yulan Piao, Jinshui Fan, Changyou Shi, Tonya Wallace, Cuong Nguyen, Isabelle A Rathbun, Rachel Munk, Dimitrios Tsitsipatis, Supriyo De, Payel Sen, Luigi Ferrucci, Myriam Gorospe.

  Tissue-resident macrophages represent a group of highly responsive innate immune cells that acquire diverse functions by polarizing towards distinct subpopulations. The subpopulations of macrophages that reside in skeletal muscle (SKM) and their changes during aging are poorly characterized. By single-cell transcriptomic analysis with unsupervised clustering, we found eleven distinct macrophage clusters in male mouse SKM with enriched gene expression programs linked to reparative, proinflammatory, phagocytotic, proliferative, and senescence-associated functions. Using a complementary classification, membrane markers LYVE1 and MHCII identified four macrophage subgroups: LYVE1-/MHCIIhi (M1-like, classically activated), LYVE1+/MHCIIlo (M2-like, alternatively activated), and two new subgroups, LYVE1+/MHCIIhi and LYVE1-/MHCIIlo. Notably, one new subgroup, LYVE1+/MHCIIhi, had traits of both M2 and M1 macrophages, while the other new subgroup, LYVE1-/MHCIIlo, displayed strong phagocytotic capacity. Flow cytometric analysis validated the presence of the four macrophage subgroups in SKM, and found that LYVE1- macrophages were more abundant than LYVE1+ macrophages in old SKM. A striking increase in proinflammatory markers (S100a8 and S100a9 mRNAs) and senescence-related markers (Gpnmb and Spp1 mRNAs) was evident in macrophage clusters from older mice. In sum, we have identified dynamically polarized SKM macrophages and propose that specific macrophage subpopulations contribute to the proinflammatory and senescent traits of old SKM.

Keywords:  cell biology; mouse

DOI:  https://doi.org/10.7554/eLife.77974
Nat Metab. 2022 Oct;4(10): 1336-1351

COX7A2L genetic variants determine cardiorespiratory fitness in mice and human.

Giorgia Benegiamo, Maroun Bou Sleiman, Martin Wohlwend, Sandra Rodríguez-López, Ludger J E Goeminne, Pirkka-Pekka Laurila, Marie Klevjer, Minna K Salonen, Jari Lahti, Pooja Jha, Sara Cogliati, José Antonio Enriquez, Ben M Brumpton, Anja Bye, Johan G Eriksson, Johan Auwerx.

Mitochondrial respiratory complexes form superassembled structures called supercomplexes. COX7A2L is a supercomplex-specific assembly factor in mammals, although its implication for supercomplex formation and cellular metabolism remains controversial. Here we identify a role for COX7A2L for mitochondrial supercomplex formation in humans. By using human cis-expression quantitative trait loci data, we highlight genetic variants in the COX7A2L gene that affect its skeletal muscle expression specifically. The most significant cis-expression quantitative trait locus is a 10-bp insertion in the COX7A2L 3' untranslated region that increases messenger RNA stability and expression. Human myotubes harboring this insertion have more supercomplexes and increased respiration. Notably, increased COX7A2L expression in the muscle is associated with lower body fat and improved cardiorespiratory fitness in humans. Accordingly, specific reconstitution of Cox7a2l expression in C57BL/6J mice leads to higher maximal oxygen consumption, increased lean mass and increased energy expenditure. Furthermore, Cox7a2l expression in mice is induced specifically in the muscle upon exercise. These findings elucidate the genetic basis of mitochondrial supercomplex formation and function in humans and show that COX7A2L plays an important role in cardiorespiratory fitness, which could have broad therapeutic implications in reducing cardiovascular mortality.

DOI: https://doi.org/10.1038/s42255-022-00655-0
Annu Rev Physiol. 2022 Oct 20.

Myostatin: A Skeletal Muscle Chalone.

Se-Jin Lee.

Myostatin (GDF-8) was discovered 25 years ago as a new transforming growth factor-β family member that acts as a master regulator of skeletal muscle mass. Myostatin is made by skeletal myofibers, circulates in the blood, and acts back on myofibers to limit growth. Myostatin appears to have all of the salient properties of a chalone, which is a term proposed over a half century ago to describe hypothetical circulating, tissue-specific growth inhibitors that control tissue size. The elucidation of the molecular, cellular, and physiological mechanisms underlying myostatin activity suggests that myostatin functions as a negative feedback regulator of muscle mass and raises the question as to whether this type of chalone mechanism is unique to skeletal muscle or whether it also operates in other tissues. Expected final online publication date for the Annual Review of Physiology, Volume 85 is February 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-physiol-012422-112116
Acta Biomater. 2022 Oct 12. pii: S1742-7061(22)00671-7. [Epub ahead of print]

Gene editing of Duchenne muscular dystrophy using biomineralization-based spCas9 variant nanoparticles.

Shuojun Li, Moqing Du, Jiamin Deng, Guiyun Deng, Jiaying Li, Zhiyong Song, Heyou Han.

  The CRISPR/Cas9 mediated genome editing have provided a promising strategy to correct multiple mutations of Duchenne muscular dystrophy (DMD). However, the delivery of CRISPR/Cas9 system into mammalian cell for DMD gene editing mainly relies on adeno associated virus (AAV)-mediated transport. Meanwhile, the protospacer adjacent motif (PAM) requirement of wild-typed Cas9 protein causing the target sites for exon splice acceptor site are restricted to limited regions. Here, we developed a biomineralized PAMLess Cas9 (SpRY) variant nanoparticles (Bm-SpRY NPs) for DMD gene editing in vitro and in vivo. This method described a facile synthesis of biomineralized NPs with high SpRY pDNA encapsulation efficiency. In vitro results show that the Bm-SpRY NPs have the obvious advantages of well biocompatibility and protecting SpRY pDNA from enzyme degradation and efficient delivery under high serum condition. Cell studies demonstrated that Bm-SpRY NPs enable rapid cellular uptake, endo-lysosomes escape and nucleus transport. Meanwhiles, the DMD gene editing via Bm-SpRY NPs pathway is transient process without genomic integration. We evaluated multiple target regions with different PAMs for the DMD exon 51 splice acceptor site through Bm-SpRY NPs method and found that the target region with TAG PAM has the highest editing efficiency and significant preferential mutation. In vivo results show that intramuscular injection of Bm-SpRY NPs enable DMD gene mutation in muscle tissue without tissue damage. This study may extend the advanced application of CRISPR system for DMD therapy. STATEMENT OF SIGNIFICANCE: The gene editing technology of CRISPR/Cas9 provides an effective treatment strategy for the Duchenne muscular dystrophy (DMD) therapy. However, the delivery of CRISPR system in mammalian cell mainly relies on viral mediated transport and the NGG or NAG requirement of wild-typed Cas9 protein limits the target region in DMD gene. Here, the present study provides a biomineralized PAM Less Cas9 (SpRY) variant nanoparticles (Bm-SpRY NPs) for DMD gene editing in vitro and in vivo. This study may extend the application of CRISPR system for DMD gene therapy.

Keywords:  Biomineralization; CRISPR/Cas9; Delivery; Duchenne muscular dystrophy; Gene editing

DOI:  https://doi.org/10.1016/j.actbio.2022.10.015
Front Physiol. 2022 ;13 992413

Increasing plasma L-kynurenine impairs mitochondrial oxidative phosphorylation prior to the development of atrophy in murine skeletal muscle: A pilot study.

Victoria R Palzkill, Trace Thome, Ania L Murillo, Ram B Khattri, Terence E Ryan.

  Introduction: L-Kynurenine (L-Kyn), a product of tryptophan (Trp) catabolism, has been linked with impairments in walking speed, muscle strength/size, and physical function. The purpose of this pilot study was to develop a dietary model that elevates plasma L-Kyn levels in mice and characterize its impact on muscle health and function. Methods: Four-month-old C57BL6J male mice were randomized to either a L-Kyn supplemented (150 mg/kg) or chow diet for 10 weeks. Plasma L-Kyn and Trp levels were measured via mass spectrometry. Primary outcomes included assessments of muscle weights, myofiber cross-sectional area (CSA), nerve-stimulated contractile performance, and mitochondrial oxidative phosphorylation (OXPHOS) and hydrogen peroxide (H2O2) production. Additional experiments in cultured myotubes explored the impact of enhancing L-Kyn metabolism. Results: Mice randomized to the L-Kyn diet displayed significant increases in plasma L-Kyn levels (p = 0.0028) and the L-Kyn/Trp ratio (p = 0.011) when compared to chow fed mice. Food intake and body weights were not different between groups. There were no detectable differences in muscle weights, myofiber CSA, or contractile performance. L-Kyn fed mice displayed reductions in mitochondrial OXPHOS (p = 0.05) and maximal ADP-stimulated respiration (p = 0.0498). In cultured myotubes, overexpression of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha prevented atrophy and proteolysis, as well as deficits in mitochondrial respiration with L-Kyn treatment. Conclusion: Dietary feeding of L-Kyn increases plasma L-Kyn levels and the L-Kyn/Trp ratio in healthy male mice. Mitochondrial impairments in muscle were observed in mice with elevated L-Kyn without changes in muscle size or function. Enhancing L-Kyn metabolism can protect against these effects in culture myotubes.

Keywords:  energetics; metabolism; mitochondria; physical function; weakness

DOI:  https://doi.org/10.3389/fphys.2022.992413
Mol Cell Endocrinol. 2022 Oct 18. pii: S0303-7207(22)00248-9. [Epub ahead of print] 111800

Insulin resistance promotes extracellular BCAA accumulation without altering LAT1 content, independent of prior BCAA treatment in a myotube model of skeletal muscle.

Caroline N Rivera, Madison M Kamer, Madison E Rivera, Rachel M Watne, Trent C Macgowan, Andrew J Wommack, Roger A Vaughan.

   PURPOSE: Type 2 diabetes is characterized by reduced insulin sensitivity which correlates with increased circulating BCAA. These experiments investigated the effects of insulin resistance with and without excess BCAA on myotube insulin sensitivity and L-type amino acid transporter-1 (LAT1).
METHODS: C2C12 myotubes were treated with or without excess BCAA for 1 or 6 days, both with and without insulin resistance. Western blot was used to assess insulin sensitivity and LAT1 content. Liquid chromatography-mass spectrometry was used to evaluate BCAA media content.
RESULTS: Insulin resistance was associated with significantly increased extracellular BCAA accumulation independent of LAT1 content. Conversely, prior BCAA treatment was not associated with extracellular BCAA accumulation regardless of level of insulin sensitivity.
CONCLUSION: These data suggest insulin resistance, but not BCAA treatment, promotes extracellular BCAA accumulation independent of changes in LAT1 content, implicating insulin resistance as a causal agent of extracellular BCAA accumulation.

Keywords:  Diabetes; Insulin resistance; Isoleucine; Leucine; Valine; pAkt/Akt

DOI:  https://doi.org/10.1016/j.mce.2022.111800
FASEB J. 2022 Nov;36(11): e22614

Recent advances in cell-based and cell-free therapeutic approaches for sarcopenia.

Shiqiang Wu, Shu Lin, Xiaolu Zhang, Mujahid Alizada, Liangmin Wang, Yiqiang Zheng, Qingfeng Ke, Jie Xu.

  Sarcopenia is a progressive loss of muscle mass and function that is connected with increased hospital expenditures, falls, fractures, and mortality. Although muscle loss has been related to aging, injury, hormonal imbalances, and diseases such as malignancies, chronic obstructive pulmonary disease, heart failure, and kidney failure, the underlying pathogenic mechanisms of sarcopenia are unclear. Exercise-based interventions and multimodal strategies are currently being considered as potential therapeutic approaches to prevent or treat these diseases. Although drug therapy research is ongoing, no drug has yet been proven to have a substantial safety and clinical value to be the first drug therapy to be licensed for sarcopenia. To better understand the molecular alterations underlying sarcopenia and effective treatments, we review leading research and available findings from the systemic change to the muscle-specific microenvironment. Furthermore, we explore possible mechanisms of sarcopenia and provide new knowledge for the development of novel cell-free and cell-based therapeutics. This review will assist researchers in developing better therapies to improve muscle health in the elderly.

Keywords:  aging; cell-based and cell-free therapeutics; exosomes; sarcopenia

DOI:  https://doi.org/10.1096/fj.202200675R
iScience. 2022 Oct 21. 25(10): 105213

Muscle atrophy phenotype gene expression during spaceflight is linked to a metabolic crosstalk in both the liver and the muscle in mice.

Geraldine Vitry, Rebecca Finch, Gavin Mcstay, Afshin Behesti, Sébastien Déjean, Tricia Larose, Virginia Wotring, Willian Abraham da Silveira.

  Human expansion in space is hampered by the physiological risks of spaceflight. The muscle and the liver are among the most affected tissues during spaceflight and their relationships in response to space exposure have never been studied. We compared the transcriptome response of liver and quadriceps from mice on NASA RR1 mission, after 37 days of exposure to spaceflight using GSEA, ORA, and sparse partial least square-differential analysis. We found that lipid metabolism is the most affected biological process between the two organs. A specific gene cluster expression pattern in the liver strongly correlated with glucose sparing and an energy-saving response affecting high energy demand process gene expression such as DNA repair, autophagy, and translation in the muscle. Our results show that impaired lipid metabolism gene expression in the liver and muscle atrophy gene expression are two paired events during spaceflight, for which dietary changes represent a possible countermeasure.

Keywords:  Astronautics; Omics; Space medicine; Space sciences

DOI:  https://doi.org/10.1016/j.isci.2022.105213
Front Endocrinol (Lausanne). 2022 ;13 989135

Irisin at the crossroads of inter-organ communications: Challenge and implications.

Renqing Zhao.

  The physiological functions of organs are intercommunicated occurring through secreted molecules. That exercise can improve the physiological function of organs or tissues is believed by secreting myokines from muscle to target remote organs. However, the underlying mechanism how exercise regulates the inter-organ communications remains incompletely understood yet. A recently identified myokine-irisin, primarily found in muscle and adipose and subsequently extending to bone, heart, liver and brain, provides a new molecular evidence for the inter-organ communications. It is secreted under the regulation of exercise and mediates the intercommunications between exercise and organs. To best our understanding of the regulatory mechanism, this review discusses the recent evidence involving the potential molecular pathways of the inter-organ communications, and the interactions between signalings and irisin in regulating the impact of exercise on organ functions are also discussed.

Keywords:  bone; brain function; exercise; heart diseases; irisin; liver

DOI:  https://doi.org/10.3389/fendo.2022.989135