bims-moremu 2023-06-18 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2023‒06‒18
28 papers selected by
Anna Vainshtein
Craft Science Inc.

Mechanisms of Skeletal Muscle Atrophy and Molecular Circuitry of Stem Cell Fate in Skeletal Muscle Regeneration and Aging.
Cyclin D3 deficiency promotes a slower, more oxidative skeletal muscle phenotype and ameliorates pathophysiology in the mdx mouse model of Duchenne muscular dystrophy.
PHAF1/MYTHO is a novel autophagy regulator that controls muscle integrity.
Satellite cell contribution to disease pathology in Duchenne muscular dystrophy.
Aging disrupts gene expression timing during muscle regeneration.
RhoA/ROCK signalling activated by ARHGEF3 promotes muscle weakness via autophagy in dystrophic mdx mice.
Identification of novel genes associated with exercise and calorie restriction effects in skeletal muscle.
Transthyretin knockdown recapitulates the insulin-sensitizing effects of exercise and promotes skeletal muscle adaptation to exercise endurance.
Maladaptive Immune Activation in Age-Related Decline of Muscle Function.
nNOS Increases Fiber Type-Specific Angiogenesis in Skeletal Muscle of Mice in Response to Endurance Exercise.
Restoration of CPEB4 prevents muscle stem cell senescence during aging.
Strength athletes and mitochondria: It's about 'time'.
Role of p53 in Cisplatin-Induced Myotube Atrophy.
MDFI regulates fast-to-slow muscle fiber type transformation via the calcium signaling pathway.
Senescent adipocytes as potential effectors of muscle cells dysfunction: An in vitro model.
A novel mitochondrial complex I ROS inhibitor partially improves muscle regeneration in adult but not old mice.
The mitochondrial calcium uniporter (MCU) activates mitochondrial respiration and enhances mobility by regulating mitochondrial redox state.
Whole-genome methylation analysis of aging human tissues identifies age-related changes in developmental and neurological pathways.
Calpain-3 Is Not a Sodium Dependent Protease and Simply Requires Calcium for Activation.
Associations of Serum CXCL12α and CK Levels with Skeletal Muscle Mass in Older Adults.
Report and Abstracts of the 19th Meeting of the Interuniversity Institute of Myology: Assisi, October 20-23, 2022.
Blockade of glucagon increases muscle mass and alters fiber type composition in mice deficient in proglucagon-derived peptides.
Multi-tissue responses to exercise: A MoTrPAC feasibility study.
Low energy availability reduces myofibrillar and sarcoplasmic muscle protein synthesis in trained females.
Proteomic analysis of the small extracellular vesicles and soluble secretory proteins from cachexia inducing and non-inducing cancer cells.
A worm's life: AMPK links muscle mitochondrial dynamics to physical fitness and healthy aging in Caenorhabditis elegans.
Advances in understanding the energetics of muscle contraction.
GLP‑1 receptor agonist protects palmitate-induced insulin resistance in skeletal muscle cells by up-regulating sestrin2 to promote autophagy.

J Gerontol A Biol Sci Med Sci. 2023 Jun 16. 78(Supplement_1): 14-18

Mechanisms of Skeletal Muscle Atrophy and Molecular Circuitry of Stem Cell Fate in Skeletal Muscle Regeneration and Aging.

Sue C Bodine, Indranil Sinha, Hugh Lee Sweeney.

  Skeletal muscle is a complex and highly adaptable tissue. With aging, there is a progressive loss of muscle mass and function, known as sarcopenia, and a reduced capacity for regeneration and repair following injury. A review of the literature shows that the primary mechanisms underlying the age-related loss of muscle mass and the attenuated growth response are multi-factorial and related to alterations in multiple processes, including proteostasis, mitochondrial function, extracellular matrix remodeling, and neuromuscular junction function. Multiple factors influence the rate of sarcopenia, including acute illness and trauma, followed by incomplete recovery and repair. Regeneration and repair of damaged skeletal muscle involve an orchestrated cross-talk between multiple cell populations, including satellite cells, immune cells, and fibro-adipogenic precursor cells. Proof-of-concept studies in mice have demonstrated that reprogramming of this disrupted orchestration, resulting in the normalization of muscle function, may be possible using small molecules that target muscle macrophages. During aging, as well as in muscular dystrophies, disruptions in multiple signaling pathways and in the cross-talk between different cell populations contribute to the failure to properly repair and maintain muscle mass and function.

Keywords:  Macrophages; Neuromuscular junction; Proteostasis; Sarcopenia; Satellite cells

DOI:  https://doi.org/10.1093/gerona/glad023
FASEB J. 2023 07;37(7): e23025

Cyclin D3 deficiency promotes a slower, more oxidative skeletal muscle phenotype and ameliorates pathophysiology in the mdx mouse model of Duchenne muscular dystrophy.

Agnese Bonato, Giada Raparelli, Siro Luvisetto, Flavia Forconi, Marianna Cosentino, Felice Tirone, Emanuele Rizzuto, Maurizia Caruso.

  We previously reported that cyclin D3-null mice display a shift toward the slow, oxidative phenotype in skeletal muscle, improved exercise endurance, and increased energy expenditure. Here, we explored the role of cyclin D3 in the physiologic response of skeletal muscle to external stimuli and in a model of muscle degenerative disease. We show that cyclin D3-null mice exhibit a further transition from glycolytic to oxidative muscle fiber type in response to voluntary exercise and an improved response to fasting. Since fast glycolytic fibers are known to be more susceptible to degeneration in Duchenne muscular dystrophy (DMD), we examined the effects of cyclin D3 inactivation on skeletal muscle phenotype in the mdx mouse model of DMD. Compared with control mdx mice, cyclin D3-deficient mdx mice display a higher proportion of slower and more oxidative myofibers, reduced muscle degenerative/regenerative processes, and reduced myofiber size variability, indicating an attenuation of dystrophic histopathology. Furthermore, mdx muscles lacking cyclin D3 exhibit reduced fatigability during repeated electrical stimulations. Notably, cyclin D3-null mdx mice show enhanced performance during recurrent trials of endurance treadmill exercise, and post-exercise muscle damage results decreased while the regenerative capacity is boosted. In addition, muscles from exercised cyclin D3-deficient mdx mice display increased oxidative capacity and increased mRNA expression of genes involved in the regulation of oxidative metabolism and the response to oxidative stress. Altogether, our findings indicate that depletion of cyclin D3 confers benefits to dystrophic muscle, suggesting that cyclin D3 inhibition may represent a promising therapeutic strategy against DMD.

Keywords:   mdx ; Duchenne muscular dystrophy; cyclin D3; exercise; oxidative metabolism; skeletal muscle fibers

DOI:  https://doi.org/10.1096/fj.202201769R
Autophagy. 2023 Jun 12. 1-3

PHAF1/MYTHO is a novel autophagy regulator that controls muscle integrity.

Anais Franco-Romero, Jean Philippe Leduc-Gaudet, Sabah Na Hussain, Gilles Gouspillou, Marco Sandri.

  Skeletal muscles play key roles in movement, posture, thermogenesis, and whole-body metabolism. Autophagy plays essential roles in the regulation of muscle mass, function and integrity. However, the molecular machinery that regulates autophagy is still incompletely understood. In our recent study, we identified and characterized a novel Forkhead Box O (FoxO)-dependent gene, PHAF1/MYTHO (phagophore assembly factor 1/macro-autophagy and youth optimizer), as a novel autophagy regulator that controls muscle integrity. MYTHO/PHAF1 is upregulated in multiple conditions leading to muscle atrophy, and downregulation of its expression spares muscle atrophy triggered by fasting, denervation, cachexia and sepsis. Overexpression of PHAF1/MYTHO is sufficient to induce muscle atrophy. Prolonged downregulation of PHAF1/MYTHO causes a severe myopathic phenotype, which is characterized by impaired autophagy, muscle weakness, myofiber degeneration, mammalian target of rapamycin complex 1 (mTORC1) hyperactivation and extensive ultrastructural defects, such as accumulation of proteinaceous and membranous structures and tubular aggregates. This myopathic phenotype is attenuated upon administration of the mTORC1 inhibitor rapamycin. These findings position PHAF1/MYTHO as a novel regulator of skeletal muscle autophagy and tissue integrity.

Keywords:  FoxO; Myopathy; autophagy; mTOR; muscle atrophy; myotonic dystrophy type 1

DOI:  https://doi.org/10.1080/15548627.2023.2224206
Front Physiol. 2023 ;14 1180980

Satellite cell contribution to disease pathology in Duchenne muscular dystrophy.

Kasun Kodippili, Michael A Rudnicki.

  Progressive muscle weakness and degeneration characterize Duchenne muscular dystrophy (DMD), a lethal, x-linked neuromuscular disorder that affects 1 in 5,000 boys. Loss of dystrophin protein leads to recurrent muscle degeneration, progressive fibrosis, chronic inflammation, and dysfunction of skeletal muscle resident stem cells, called satellite cells. Unfortunately, there is currently no cure for DMD. In this mini review, we discuss how satellite cells in dystrophic muscle are functionally impaired, and how this contributes to the DMD pathology, and the tremendous potential of restoring endogenous satellite cell function as a viable treatment strategy to treat this debilitating and fatal disease.

Keywords:  Duchenne muscular dystrophy; asymmetric cell division; dystrophin; muscle regeneration; myogenesis; satellite cells; skeletal muscle stem cells; symmetric cell division

DOI:  https://doi.org/10.3389/fphys.2023.1180980
Stem Cell Reports. 2023 Jun 13. pii: S2213-6711(23)00183-2. [Epub ahead of print]18(6): 1325-1339

Aging disrupts gene expression timing during muscle regeneration.

Jesse V Kurland, Alicia A Cutler, Jacob T Stanley, Nicole Dalla Betta, Ashleigh Van Deusen, Brad Pawlikowski, Monica Hall, Tiffany Antwine, Alan Russell, Mary Ann Allen, Robin Dowell, Bradley Olwin.

  Skeletal muscle function and regenerative capacity decline during aging, yet factors driving these changes are incompletely understood. Muscle regeneration requires temporally coordinated transcriptional programs to drive myogenic stem cells to activate, proliferate, fuse to form myofibers, and to mature as myonuclei, restoring muscle function after injury. We assessed global changes in myogenic transcription programs distinguishing muscle regeneration in aged mice from young mice by comparing pseudotime trajectories from single-nucleus RNA sequencing of myogenic nuclei. Aging-specific differences in coordinating myogenic transcription programs necessary for restoring muscle function occur following muscle injury, likely contributing to compromised regeneration in aged mice. Differences in pseudotime alignment of myogenic nuclei when comparing aged with young mice via dynamic time warping revealed pseudotemporal differences becoming progressively more severe as regeneration proceeds. Disruptions in timing of myogenic gene expression programs may contribute to incomplete skeletal muscle regeneration and declines in muscle function as organisms age.

Keywords:  MuSC; aging; cell fate; differentiation; myonuclei; pseudotime; regeneration; single-nucleus RNA sequencing; skeletal muscle regeneration

DOI:  https://doi.org/10.1016/j.stemcr.2023.05.005
J Cachexia Sarcopenia Muscle. 2023 Jun 13.

RhoA/ROCK signalling activated by ARHGEF3 promotes muscle weakness via autophagy in dystrophic mdx mice.

Jae-Sung You, Yongdeok Kim, Soohyun Lee, Rashid Bashir, Jie Chen.

  BACKGROUND: Duchenne muscular dystrophy (DMD), caused by dystrophin deficiency, leads to progressive and fatal muscle weakness through yet-to-be-fully deciphered molecular perturbations. Emerging evidence implicates RhoA/Rho-associated protein kinase (ROCK) signalling in DMD pathology, yet its direct role in DMD muscle function, and related mechanisms, are unknown.METHODS: Three-dimensionally engineered dystrophin-deficient mdx skeletal muscles and mdx mice were used to test the role of ROCK in DMD muscle function in vitro and in situ, respectively. The role of ARHGEF3, one of the RhoA guanine nucleotide exchange factors (GEFs), in RhoA/ROCK signalling and DMD pathology was examined by generating Arhgef3 knockout mdx mice. The role of RhoA/ROCK signalling in mediating the function of ARHGEF3 was determined by evaluating the effects of wild-type or GEF-inactive ARHGEF3 overexpression with ROCK inhibitor treatment. To gain more mechanistic insights, autophagy flux and the role of autophagy were assessed in various conditions with chloroquine.
RESULTS: Inhibition of ROCK with Y-27632 improved muscle force production in 3D-engineered mdx muscles (+25% from three independent experiments, P < 0.05) and in mice (+25%, P < 0.001). Unlike suggested by previous studies, this improvement was independent of muscle differentiation or quantity and instead related to increased muscle quality. We found that ARHGEF3 was elevated and responsible for RhoA/ROCK activation in mdx muscles, and that depleting ARHGEF3 in mdx mice restored muscle quality (up to +36%, P < 0.01) and morphology without affecting regeneration. Conversely, overexpressing ARHGEF3 further compromised mdx muscle quality (-13% vs. empty vector control, P < 0.01) in GEF activity- and ROCK-dependent manner. Notably, ARHGEF3/ROCK inhibition exerted the effects by rescuing autophagy which is commonly impaired in dystrophic muscles.
CONCLUSIONS: Our findings uncover a new pathological mechanism of muscle weakness in DMD involving the ARHGEF3-ROCK-autophagy pathway and the therapeutic potential of targeting ARHGEF3 in DMD.

Keywords:  Chloroquine; Engineered muscle; Force; Mdx; Regeneration; XPLN

DOI:  https://doi.org/10.1002/jcsm.13278
Aging (Albany NY). 2023 Jun 12. 15

Identification of novel genes associated with exercise and calorie restriction effects in skeletal muscle.

Jae Sook Kang, Min Ju Kim, Eun-Soo Kwon, Kwang-Pyo Lee, Chuna Kim, Ki-Sun Kwon, Yong Ryoul Yang.

  Exercise and caloric restriction (CR) significantly increase longevity across a range of species and delay aging-related losses in organ function. Although both interventions enhance skeletal muscle function, the molecular mechanisms underlying these associations are unknown. We sought to identify genes regulated by CR and exercise in muscle, and investigate their relationship with muscle function. To do this, expression profiles of Gene Expression Omnibus datasets obtained from the muscle tissue of calorie-restricted male primates and young men post-exercise were analyzed. There were seven transcripts (ADAMTS1, CPEB4, EGR2, IRS2, NR4A1, PYGO1, and ZBTB43) that were consistently upregulated by both CR and exercise training. We used C2C12 murine myoblasts to investigate the effect of silencing these genes on myogenesis, mitochondrial respiration, autophagy, and insulin signaling, all of which are processes affected by CR and exercise. Our results show that in C2C12 cells, Irs2 and Nr4a1 expression were critical for myogenesis, and five genes (Egr2, Irs2, Nr4a1, Pygo1, and ZBTB43) regulated mitochondrial respiration while having no effect on autophagy. Cpeb4 knockdown increased the expression of genes involved in muscle atrophy and induced myotube atrophy. These findings suggest new resources for studying the mechanisms underlying the beneficial effects of exercise and calorie restriction on skeletal muscle function and lifespan extension.

Keywords:  calorie restriction; exercise; insulin sensitivity; mitochondrial respiration; muscle atrophy; myogenesis

DOI:  https://doi.org/10.18632/aging.204793
J Mol Endocrinol. 2023 Jul 01. pii: e220163. [Epub ahead of print]71(1):

Transthyretin knockdown recapitulates the insulin-sensitizing effects of exercise and promotes skeletal muscle adaptation to exercise endurance.

Beibei Wu, Ruojun Qiu, Shuo Wang, Yingzi He, Jing Wang, Zhiye Xu, Xihua Lin, Hong Li, Fenping Zheng.

  Liver transthyretin (TTR) synthesis and release are exacerbated in insulin-resistant states but are decreased by exercise training, in relation to the insulin-sensitizing effects of exercise. We hypothesized that TTR knockdown (TTR-KD) may mimic this exercise-induced metabolic improvement and skeletal muscle remodeling. Adeno-associated virus-mediated TTR-KD and control mice were trained for 8 weeks on treadmills. Their metabolism status and exercise capacity were investigated and then compared with sedentary controls. After treadmill training, the mice showed improved glucose and insulin tolerance, hepatic steatosis, and exercise endurance. Sedentary TTR-KD mice displayed metabolic improvements comparable to the improvements in trained mice. Both exercise training and TTR-KD promoted the oxidative myofiber compositions of MyHC I and MyHC IIa in the quadriceps and gastrocnemius skeletal muscles. Furthermore, training and TTR-KD had an additive effect on running performance, accompanied by substantial increases in oxidative myofiber composition, Ca2+-dependent Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity, and the downstream expression of PGC1α as well as the unfolded protein response (UPR) segment of PERK-p-eIF2a pathway activity. Consistent with these findings, electrical pulse stimulation of an in vitro model of chronic exercise (with differentiated C2C12 myoblasts) showed that exogenous TTR protein was internalized and localized in the endoplasmic reticulum, where it disrupted Ca2+ dynamics; this led to decreases in intracellular Ca2+ concentration and downstream pathway activity. TTR-KD may function as an exercise/Ca2+-dependent CaMKII-PGC1α-UPR regulator that upregulates the oxidative myofiber composition of fast-type muscles; it appears to mimic the effect of exercise training on insulin sensitivity-related metabolic improvement and endurance capacity.

Keywords:  Ca2+-dependent signaling; PGC1α; UPR; exercise; insulin resistance; transthyretin

DOI:  https://doi.org/10.1530/JME-22-0163
J Gerontol A Biol Sci Med Sci. 2023 Jun 16. 78(Supplement_1): 19-24

Maladaptive Immune Activation in Age-Related Decline of Muscle Function.

Monty Montano, Rosaly Correa-de-Araujo.

  Age-related changes in immune competency and inflammation play a role in the decline of physical function. In this review of the conference on Function-Promoting Therapies held in March 2022, we discuss the biology of aging and geroscience with an emphasis on decline in physical function and the role of age-related changes in immune competence and inflammation. More recent studies in skeletal muscle and aging highlighting a crosstalk between skeletal muscle, neuromuscular feedback, and immune cell subsets are also discussed. The value of strategies targeting specific pathways that affect skeletal muscle and more systems-wide approaches that provide benefits in muscle homeostasis with aging are underscored. Goals in clinical trial design and the need for incorporating differences in life history when interpreting results from these intervention strategies are important. Where applicable, references are made to papers presented at the conference. We conclude by underscoring the need to incorporate age-related immune competency and inflammation when interpreting results from interventions that target specific pathways predicted to promote skeletal muscle function and tissue homeostasis.

Keywords:  Functional decline; Immune system; Inflammaging; Sarcopenia; Skeletal muscle

DOI:  https://doi.org/10.1093/gerona/glad036
Int J Mol Sci. 2023 May 26. pii: 9341. [Epub ahead of print]24(11):

nNOS Increases Fiber Type-Specific Angiogenesis in Skeletal Muscle of Mice in Response to Endurance Exercise.

Oliver Baum, Felicitas A M Huber-Abel, Martin Flück.

  We studied the relationship between neuronal NO synthase (nNOS) expression and capillarity in the tibialis anterior (TA) muscle of mice subjected to treadmill training. The mRNA (+131%) and protein (+63%) levels of nNOS were higher (p ≤ 0.05) in the TA muscle of C57BL/6 mice undergoing treadmill training for 28 days than in those of littermates remaining sedentary, indicating an up-regulation of nNOS by endurance exercise. Both TA muscles of 16 C57BL/6 mice were subjected to gene electroporation with either the pIRES2-ZsGreen1 plasmid (control plasmid) or the pIRES2-ZsGreen1-nNOS gene-inserted plasmid (nNOS plasmid). Subsequently, one group of mice (n = 8) underwent treadmill training for seven days, while the second group of mice (n = 8) remained sedentary. At study end, 12-18% of TA muscle fibers expressed the fluorescent reporter gene ZsGreen1. Immunofluorescence for nNOS was 23% higher (p ≤ 0.05) in ZsGreen1-positive fibers than ZsGreen1-negative fibers from the nNOS-transfected TA muscle of mice subjected to treadmill training. Capillary contacts around myosin heavy-chain (MHC)-IIb immunoreactive fibers (14.2%; p ≤ 0.05) were only higher in ZsGreen1-positive fibers than ZsGreen1-negative fibers in the nNOS-plasmid-transfected TA muscles of trained mice. Our observations are in line with an angiogenic effect of quantitative increases in nNOS expression, specifically in type-IIb muscle fibers after treadmill training.

Keywords:  angiogenesis; capillary; endurance exercise; nNOS; nitric oxide; skeletal muscle

DOI:  https://doi.org/10.3390/ijms24119341
Dev Cell. 2023 Jun 08. pii: S1534-5807(23)00244-7. [Epub ahead of print]

Restoration of CPEB4 prevents muscle stem cell senescence during aging.

Wenshu Zeng, Wenxin Zhang, Erin H Y Tse, Jing Liu, Anqi Dong, Kim S W Lam, Shaoyuan Luan, Wai Hing Kung, Tsz Ching Chan, Tom H Cheung.

  Age-associated impairments in adult stem cell functions correlate with a decline in somatic tissue regeneration capacity. However, the mechanisms underlying the molecular regulation of adult stem cell aging remain elusive. Here, we provide a proteomic analysis of physiologically aged murine muscle stem cells (MuSCs), illustrating a pre-senescent proteomic signature. During aging, the mitochondrial proteome and activity are impaired in MuSCs. In addition, the inhibition of mitochondrial function results in cellular senescence. We identified an RNA-binding protein, CPEB4, downregulated in various aged tissues, which is required for MuSC functions. CPEB4 regulates the mitochondrial proteome and activity through mitochondrial translational control. MuSCs devoid of CPEB4 induced cellular senescence. Importantly, restoring CPEB4 expression rescued impaired mitochondrial metabolism, improved geriatric MuSC functions, and prevented cellular senescence in various human cell lines. Our findings provide the basis for the possibility that CPEB4 regulates mitochondrial metabolism to govern cellular senescence, with an implication of therapeutic intervention for age-related senescence.

Keywords:  CPEB4; aging; mitochondrial metabolism; muscle stem cells; quiescence; senescence

DOI:  https://doi.org/10.1016/j.devcel.2023.05.012
J Physiol. 2023 Jun 12.

Strength athletes and mitochondria: It's about 'time'.

Madison C Garibotti, Christopher G R Perry.



Keywords:  exercise; mitochondria; muscle

DOI:  https://doi.org/10.1113/JP284856
Int J Mol Sci. 2023 May 24. pii: 9176. [Epub ahead of print]24(11):

Role of p53 in Cisplatin-Induced Myotube Atrophy.

Chinami Matsumoto, Hitomi Sekine, Nana Zhang, Sachiko Mogami, Naoki Fujitsuka, Hiroshi Takeda.

  Chemotherapy-induced sarcopenia is an unfavorable prognostic factor implicated in the development of postoperative complications and reduces the quality of life of patients with cancer. Skeletal muscle loss due to cisplatin use is caused by mitochondrial dysfunction and activation of muscle-specific ubiquitin ligases Atrogin-1 and muscle RING finger 1 (MuRF1). Although animal studies suggest the involvement of p53 in age-, immobility-, and denervation-related muscle atrophy, the association between cisplatin-induced atrophy and p53 remains unknown. Herein, we investigated the effect of a p53-specific inhibitor, pifithrin-alpha (PFT-α), on cisplatin-induced atrophy in C2C12 myotubes. Cisplatin increased the protein levels of p53, phosphorylated p53, and upregulated the mRNA expression of p53 target genes PUMA and p21 in C2C12 myotubes. PFT-α ameliorated the increase in intracellular reactive oxygen species production and mitochondrial dysfunction, and also reduced the cisplatin-induced increase in the Bax/Bcl-2 ratio. Although PFT-α also reduced the cisplatin-induced increase in MuRF1 and Atrogin-1 gene expression, it did not ameliorate the decrease in myosin heavy chain mRNA and protein levels and muscle-specific actin and myoglobin protein levels. We conclude that cisplatin increases muscle degradation in C2C12 myotubes in a p53-dependent manner, but p53 has minimal involvement in the reduction of muscle protein synthesis.

Keywords:  C2C12 myotube; atrophy; cisplatin; p53; pifithrin-alpha

DOI:  https://doi.org/10.3390/ijms24119176
Biochem Biophys Res Commun. 2023 Jun 01. pii: S0006-291X(23)00616-2. [Epub ahead of print]671 215-224

MDFI regulates fast-to-slow muscle fiber type transformation via the calcium signaling pathway.

Tingting Lu, Yifan Zhu, Jiali Guo, Ziyuan Mo, Quan Zhou, Ching Yuan Hu, Chong Wang.

  Muscle fiber is the basic unit of skeletal muscle with strong self-adaptability, and its type is closely related to meat quality. Myod family inhibitor (Mdfi) has the function of regulating myogenic regulatory factors during cell differentiation, but how Mdfi regulates muscle fiber type transformation in myoblasts is still unclear. In the present study, we constructed overexpressing and interfering with Mdfi C2C12 cell models by lipofection. The immunofluorescence, quantitative real-time PCR (qPCR), and western blot results show that the elevated MDFI promoted mitochondrial biogenesis, aerobic metabolism and the calcium level by activating CaMKK2 and AMPK phosphorylation and then stimulated the conversion of C2C12 cells from fast glycolytic to slow oxidative type. In addition, after inhibiting IP3R and RYR channels, the higher MDFI reversed the blockage of calcium release from the endoplasmic reticulum by calcium channel receptor inhibitors and increased intracellular calcium levels. Therefore, we propose that the higher MDFI promotes muscle fiber types conversion through the calcium signaling pathway. These findings further broaden our understanding of the regulatory mechanism of MDFI in muscle fiber type transformation. Furthermore, our results suggest potential therapeutic targets for skeletal muscle and metabolic-related diseases.

Keywords:  Calcium signaling pathway; Endoplasmic reticulum calcium channel; MDFI; Muscle fiber type conversion

DOI:  https://doi.org/10.1016/j.bbrc.2023.05.053
Exp Gerontol. 2023 Jun 13. pii: S0531-5565(23)00154-7. [Epub ahead of print] 112233

Senescent adipocytes as potential effectors of muscle cells dysfunction: An in vitro model.

Zoico Elena, Saatchi Tanaz, Nori Nicole, Mazzali Gloria, Rizzatti Vanni, Pizzi Eleonora, Fantin Francesco, Giani Anna, Urbani Silvia, Zamboni Mauro.

  Recently, there has been a growing body of evidence showing a negative effect of the white adipose tissue (WAT) dysfunction on the skeletal muscle function and quality. However, little is known about the effects of senescent adipocytes on muscle cells. Therefore, to explore potential mechanisms involved in age-related loss of muscle mass and function, we performed an in vitro experiment using conditioned medium obtained from cultures of mature and aged 3 T3-L1 adipocytes, as well as from cultures of dysfunctional adipocytes exposed to oxidative stress or high insulin doses, to treat C2C12 myocytes. The results from morphological measures indicated a significant decrease in diameter and fusion index of myotubes after treatment with medium of aged or stressed adipocytes. Aged and stressed adipocytes presented different morphological characteristics as well as a different gene expression profile of proinflammatory cytokines and ROS production. In myocytes treated with different adipocytes' conditioned media, we demonstrated a significant reduction of gene expression of myogenic differentiation markers as well as a significant increase of genes involved in atrophy. Finally, a significant reduction in protein synthesis as well as a significant increase of myostatin was found in muscle cells treated with medium of aged or stressed adipocytes compared to controls. In conclusion, these preliminary results suggest that aged adipocytes could influence negatively trophism, function and regenerative capacity of myocytes by a paracrine network of signaling.

Keywords:  Adipose tissue; Aging; Myostatin; Senescence; Skeletal muscle

DOI:  https://doi.org/10.1016/j.exger.2023.112233
Redox Biol. 2023 Jun 02. pii: S2213-2317(23)00171-4. [Epub ahead of print]64 102770

A novel mitochondrial complex I ROS inhibitor partially improves muscle regeneration in adult but not old mice.

Gavin Pharaoh, Ethan L Ostrom, Rudy Stuppard, Matthew Campbell, Jens Markus Borghardt, Michael Franti, Antonio Filareto, David J Marcinek.

  It is unclear whether mitochondrial dysfunction and redox stress contribute to impaired age-related muscle regenerative capacity. Here we characterized a novel compound, BI4500, that inhibits the release of reactive oxygen species (ROS) from the quinone site in mitochondrial complex I (site IQ). We tested the hypothesis that ROS release from site IQ contributes to impaired regenerative capacity in aging muscle. Electron transfer system site-specific ROS production was measured in adult and aged mouse isolated muscle mitochondria and permeabilized gastrocnemius fibers. BI4500 inhibited ROS production from site IQ in a concentration-dependent manner (IC50 = ∼985 nM) by inhibiting ROS release without impairing complex I-linked respiration. In vivo BI4500 treatment decreased ROS production from site IQ. Muscle injury and sham injury were induced using barium chloride or vehicle injection to the tibialis anterior (TA) muscle in adult and aged male mice. On the same day as injury, mice began a daily gavage of 30 mg/kg BI4500 (BI) or placebo (PLA). Muscle regeneration (H&E, Sirius Red, Pax7) was measured at 5 and 35 days after injury. Muscle injury increased centrally nucleated fibers (CNFs) and fibrosis with no treatment or age effect. There was a significant age by treatment interaction for CNFs at 5- and 35-days post injury with significantly more CNFs in BI adults compared to PLA adults. Muscle fiber cross-sectional area (CSA) recovered significantly more in adult BI mice (-89 ± 365 μm2) compared to old PLA (-599 ± 153 μm2) and old BI (-535 ± 222 μm2, mean ± SD). In situ TA force recovery was measured 35 days after injury and was not significantly different by age or treatment. Inhibition of site IQ ROS partially improves muscle regeneration in adult but not old muscle demonstrating a role for CI ROS in the response to muscle injury. Site IQ ROS does not contribute to impaired regenerative capacity in aging.

Keywords:  Barium chloride injury; Mitochondrial reactive oxygen species (ROS); Muscle injury and regeneration; Reverse electron transport (RET); Sarcopenia

DOI:  https://doi.org/10.1016/j.redox.2023.102770
Redox Biol. 2023 Jun 04. pii: S2213-2317(23)00160-X. [Epub ahead of print]64 102759

The mitochondrial calcium uniporter (MCU) activates mitochondrial respiration and enhances mobility by regulating mitochondrial redox state.

Anna Weiser, Aurélie Hermant, Flavien Bermont, Federico Sizzano, Sonia Karaz, Pilar Alvarez-Illera, Jaime Santo-Domingo, Vincenzo Sorrentino, Jerome N Feige, Umberto De Marchi.

  Regulation of mitochondrial redox balance is emerging as a key event for cell signaling in both physiological and pathological conditions. However, the link between the mitochondrial redox state and the modulation of these conditions remains poorly defined. Here, we discovered that activation of the evolutionary conserved mitochondrial calcium uniporter (MCU) modulates mitochondrial redox state. By using mitochondria-targeted redox and calcium sensors and genetic MCU-ablated models, we provide evidence of the causality between MCU activation and net reduction of mitochondrial (but not cytosolic) redox state. Redox modulation of redox-sensitive groups via MCU stimulation is required for maintaining respiratory capacity in primary human myotubes and C. elegans, and boosts mobility in worms. The same benefits are obtained bypassing MCU via direct pharmacological reduction of mitochondrial proteins. Collectively, our results demonstrate that MCU regulates mitochondria redox balance and that this process is required to promote the MCU-dependent effects on mitochondrial respiration and mobility.

Keywords:  C. elegans; Calcium signaling; MCU; Mitochondria; Redox biology; Skeletal muscle

DOI:  https://doi.org/10.1016/j.redox.2023.102759
Aging Cell. 2023 Jun 12. e13847

Whole-genome methylation analysis of aging human tissues identifies age-related changes in developmental and neurological pathways.

Ravi Tharakan, Ceereena Ubaida-Mohien, Christopher Dunn, Mary Kaileh, Rakel Tryggvadottir, Linda Zukley, Chee W Chia, Ranjan Sen, Luigi Ferrucci.

  Age-associated changes in the DNA methylation state can be used to assess the pace of aging. However, it is not understood what mechanisms drive these changes and whether these changes affect the development of aging phenotypes and the aging process in general. This study was aimed at gaining a more comprehensive understanding of aging-related methylation changes across the whole genome, and relating these changes to biological functions. It has been shown that skeletal muscle and blood monocytes undergo typical changes with aging. Using whole-genome bisulfite sequencing, we sought to characterize the genome-wide changes in methylation of DNA derived from both skeletal muscle and blood monocytes, and link these changes to specific genes and pathways through enrichment analysis. We found that methylation changes occur with aging at the locations enriched for developmental and neuronal pathways regulated in these two peripheral tissues. These results contribute to our understanding of changes in epigenome in human aging.

Keywords:  aging; epigenome; monocytes; skeletal muscle

DOI:  https://doi.org/10.1111/acel.13847
Int J Mol Sci. 2023 May 28. pii: 9405. [Epub ahead of print]24(11):

Calpain-3 Is Not a Sodium Dependent Protease and Simply Requires Calcium for Activation.

Stefan G Wette, Graham D Lamb, Robyn M Murphy.

  Calpain-3 (CAPN3) is a muscle-specific member of the calpain family of Ca2+-dependent proteases. It has been reported that CAPN3 can also be autolytically activated by Na+ ions in the absence of Ca2+, although this was only shown under non-physiological ionic conditions. Here we confirm that CAPN3 does undergo autolysis in the presence of high [Na+], but this only occurred if all K+ normally present in a muscle cell was absent, and it did not occur even in 36 mM Na+, higher than what would ever be reached in exercising muscle if normal [K+] was present. CAPN3 in human muscle homogenates was autolytically activated by Ca2+, with ~50% CAPN3 autolysing in 60 min in the presence of 2 µM Ca2+. In comparison, autolytic activation of CAPN1 required about 5-fold higher [Ca2+] in the same conditions and tissue. After it was autolysed, CAPN3 unbound from its tight binding on titin and became diffusible, but only if the autolysis led to complete removal of the IS1 inhibitory peptide within CAPN3, reducing the C-terminal fragment to 55 kDa. Contrary to a previous report, activation of CAPN3, either by raised [Ca2+] or Na+ treatment, did not cause proteolysis of the skeletal muscle Ca2+ release channel-ryanodine receptor, RyR1, in physiological ionic conditions. Treatment of human muscle homogenates with high [Ca2+] caused autolytic activation of CAPN1, accompanied by proteolysis of some titin and complete proteolysis of junctophilin (JP1, full length ~95 kDa), generating an equimolar amount of a diffusible ~75 kDa N-terminal JP1 fragment, but without any proteolysis of RyR1.

Keywords:  junctophilin; proteolytic activity; ryanodine receptor; skeletal muscle; titin fragments

DOI:  https://doi.org/10.3390/ijms24119405
J Clin Med. 2023 May 31. pii: 3800. [Epub ahead of print]12(11):

Associations of Serum CXCL12α and CK Levels with Skeletal Muscle Mass in Older Adults.

Ze Chen, Thea Laurentius, Yvonne Fait, Aline Müller, Eva Mückter, Leo Cornelius Bollheimer, Mahtab Nourbakhsh.

  Sarcopenia, a condition characterized by gradual loss of skeletal muscle mass and function, is a complex diagnosis; the decisive criterion in this diagnosis is the measurement of appendicular skeletal muscle index (ASMI). To identify potential serum markers predictive of sarcopenia in older adults, we evaluated correlations between ASMI, clinical data, and 34 serum inflammation markers in 80 older adults. Pearson's correlation analyses confirmed that ASMI was positively correlated with nutritional status (p = 0.001) and serum creatine kinase (CK) (p = 0.019) but negatively correlated with serum CXCL12α (p = 0.023), a chemoattractant for muscle stem cells. In the case group, ASMI was negatively correlated with serum interleukin (IL)-7 (p = 0.024), a myokine expressed and secreted from skeletal muscle cells in vitro. Multivariate binary logistic regression analyses identified four risk factors for sarcopenia in our study: advanced age (p = 0.012), malnutrition (p = 0.038), low serum CK levels (p = 0.044), and high serum CXCL12α levels (p = 0.029). Low CK and high CXCL12α levels serve as combinatorial serum markers of sarcopenia in older adults. The linear correlation between ASMI and CXCL12α levels may facilitate the development of new regression models for future studies on sarcopenia.

Keywords:  chemokines; creatine kinase; cytokines; geriatrics; inflammation; skeletal muscle

DOI:  https://doi.org/10.3390/jcm12113800
Eur J Transl Myol. 2023 Jun 16.

Report and Abstracts of the 19th Meeting of the Interuniversity Institute of Myology: Assisi, October 20-23, 2022.

Maurilio Sampaoleosi, Stefania Fulle.

After two years of conferences on a virtual platform due to the COVID-19 pandemic, finally, the 19th annual meeting of the Interuniversity Institute of Myology (IIM) has returned to the heart of central Italy, in Assisi, an important cultural hub, which boasts a wide range of historic buildings and museums. This event brought together scientists from around the world providing a valuable opportunity to discuss scientific issues in the field of myology. Traditionally, the meeting particularly encourages the participation of young trainees, and the panel discussions were moderated by leading international scientists, making this a special event where young researchers had the opportunity to talk to prestigious scientists in a friendly and informal environment. Furthermore, the IIM young researchers' winners for the best oral and poster presentations, became part of the IIM Young Committee, involved in the scientific organization of sessions and roundtables and for the invitation of a main speaker for the IIM 2023 meeting. The four keynote speakers for the IIM Conference 2022 presented new insights into the role of multinucleation during muscle growth and disease, the long-range distribution of giant mRNAs in skeletal muscle, human skeletal muscle remodelling from type 2 diabetic patients and the genome integrity and cell identity in adult muscle stem cells. The congress hosted young PhD students and trainees and included 6 research sessions, two poster sessions, round tables and socio-cultural events, promoting science outreach and interdisciplinary works that are advancing new directions in the field of myology. All other attendees had the opportunity to showcase their work through poster presentations. The IIM meeting 2022 was also part of an advanced training event, which included dedicated round tables and a training session of Advanced Myology on the morning of 23 October, reserved for students under 35 enrolled in the training school, receiving a certificate of attendance. This course proposed lectures and roundtable discussions coordinated by internationally outstanding speakers on muscle metabolism, pathophysiological regeneration and emerging therapeutic approaches for muscle degenerations. As in past editions, all participants shared their results, opinions, and perspectives in understanding developmental and adult myogenesis with novel insights into muscle biology in pathophysiological conditions. We report here the abstracts of the meeting that describe the basic, translational, and clinical research and certainly contribute to the vast field of myology in an innovative and original way.

DOI: https://doi.org/10.4081/ejtm.2023.11321
J Diabetes Investig. 2023 Jun 09.

Blockade of glucagon increases muscle mass and alters fiber type composition in mice deficient in proglucagon-derived peptides.

Shinji Ueno, Yusuke Seino, Shihomi Hidaka, Masashi Nakatani, Keisuke Hitachi, Naoya Murao, Yasuhiro Maeda, Haruki Fujisawa, Megumi Shibata, Takeshi Takayanagi, Katsumi Iizuka, Daisuke Yabe, Yoshihisa Sugimura, Kunihiro Tsuchida, Yoshitaka Hayashi, Atsushi Suzuki.

  AIMS/INTRODUCTION: Glucagon is secreted from pancreatic α-cells and plays an important role in amino acid metabolism in liver. Various animal models deficient in glucagon action show hyper-amino acidemia and α-cell hyperplasia, indicating that glucagon contributes to feedback regulation between the liver and the α-cells. In addition, both insulin and various amino acids, including branched-chain amino acids and alanine, participate in protein synthesis in skeletal muscle. However, the effect of hyperaminoacidemia on skeletal muscle has not been investigated. In the present study, we examined the effect of blockade of glucagon action on skeletal muscle using mice deficient in proglucagon-derived peptides (GCGKO mice).MATERIALS AND METHODS: Muscles isolated from GCGKO and control mice were analyzed for their morphology, gene expression and metabolites.
RESULTS: GCGKO mice showed muscle fiber hypertrophy, and a decreased ratio of type IIA and an increased ratio of type IIB fibers in the tibialis anterior. The expression levels of myosin heavy chain (Myh) 7, 2, 1 and myoglobin messenger ribonucleic acid were significantly lower in GCGKO mice than those in control mice in the tibialis anterior. GCGKO mice showed a significantly higher concentration of arginine, asparagine, serine and threonine in the quadriceps femoris muscles, and also alanine, aspartic acid, cysteine, glutamine, glycine and lysine, as well as four amino acids in gastrocnemius muscles.
CONCLUSIONS: These results show that hyperaminoacidemia induced by blockade of glucagon action in mice increases skeletal muscle weight and stimulates slow-to-fast transition in type II fibers of skeletal muscle, mimicking the phenotype of a high-protein diet.

Keywords:  Amino acid; Glucagon; Skeletal muscle

DOI:  https://doi.org/10.1111/jdi.14032
J Appl Physiol (1985). 2023 Jun 15.

Multi-tissue responses to exercise: A MoTrPAC feasibility study.

Toby L Chambers, Andrew M Stroh, Clarisa Chavez, Anna R Brandt, Alex Claiborne, William A Fountain, Kevin J Gries, Andrew M Jones, Dillon J Kuszmaul, Gary E Lee, Bridget E Lester, Colleen E Lynch, Kiril Minchev, Cristhian F Montenegro, Masatoshi Naruse, Ulrika Raue, Todd A Trappe, Scott Trappe.

  We assessed the feasibility of the Molecular Transducers of Physical Activity Consortium (MoTrPAC) human adult clinical exercise protocols, while also documenting select cardiovascular, metabolic, and molecular responses to these protocols. After phenotyping and familiarization sessions, 20 subjects (25±2yr, 12M, 8W) completed an endurance exercise bout (n=8, 40 min cycling at 70% VO2max), a resistance exercise bout (n=6, ~45 min, 3 sets of ~10 repetition maximum, 8 exercises), or a resting control period (n=6, 40 min rest). Blood samples were taken before, during, and after (10 min, 2h, 3.5h) exercise or rest for levels of catecholamines, cortisol, glucagon, insulin, glucose, free fatty acids, and lactate. Heart rate was recorded throughout exercise (or rest). Skeletal muscle (vastus lateralis) and adipose (peri-umbilical) biopsies were taken before and ~4h following exercise or rest for mRNA levels of genes related to energy metabolism, growth, angiogenesis, and circadian processes. Coordination of the timing of procedural components (e.g., local anesthetic delivery, biopsy incisions, tumescent delivery, intravenous line flushes, sample collection and processing, exercise transitions, and team dynamics) were reasonable to orchestrate while considering subject burden and scientific objectives. The cardiovascular and metabolic alterations reflected a dynamic and unique response to endurance and resistance exercise, while skeletal muscle was transcriptionally more responsive than adipose 4h post-exercise. In summary, the current report provides the first evidence of protocol execution and feasibility of key components of the MoTrPAC human adult clinical exercise protocols. Scientists should consider designing exercise studies in various populations to interface with the MoTrPAC protocols and DataHub.

Keywords:  MoTrPAC; adipose; gene expression; metabolism; skeletal muscle

DOI:  https://doi.org/10.1152/japplphysiol.00210.2023
J Physiol. 2023 Jun 16.

Low energy availability reduces myofibrillar and sarcoplasmic muscle protein synthesis in trained females.

Mikkel Oxfeldt, Stuart M Phillips, Ole Emil Andersen, Frank Ted Johansen, Maj Bangshaab, Jeyanthini Risikesan, James McKendry, Anna Katarina Melin, Mette Hansen.

  Low energy availability (LEA) describes a state where energy intake is insufficient to cover the energy costs of both exercise energy expenditure and basal physiological body functions. LEA has been associated with various physiological consequences, such as reproductive dysfunction. However, the effect of LEA on skeletal muscle protein synthesis in females performing exercise training is still poorly understood. We conducted a randomized controlled trial investigating the impact of LEA on daily integrated myofibrillar and sarcoplasmic muscle protein synthesis in trained females. Thirty eumenorrheic females were matched based on training history and randomized to undergo 10 days of LEA (25 kcal · kg Fat-Free Mass (FFM)-1 · day-1 ) or optimal energy availability (OEA, 50 kcal · kg FFM-1 · day-1 ). Before the intervention, both groups underwent a five-day 'run-in' period with OEA. All foods were provided throughout the experimental period with a protein content of 2.2 g · kg lean mass-1 · day-1 . A standardized, supervised combined resistance and cardiovascular exercise training program was performed over the experimental period. Daily integrated muscle protein synthesis was measured by deuterium oxide (D2 O) consumption along with changes in body composition, resting metabolic rate, blood biomarkers, and 24h nitrogen balance. We found that LEA reduced daily integrated myofibrillar and sarcoplasmic muscle protein synthesis compared to OEA. Concomitant reductions were observed in lean mass, urinary nitrogen balance, free androgen index, thyroid hormone concentrations, and resting metabolic rate following LEA. These results highlight that LEA may negatively affect skeletal muscle adaptations in females performing exercise training. KEY POINTS: Low energy availability with potential health and performance impairments is widespread among female athletes. We investigated the impact of 10 days of LEA on daily integrated myofibrillar and sarcoplasmic muscle protein synthesis in young, trained females. We show that LEA impairs myofibrillar and sarcoplasmic muscle protein synthesis in trained females performing exercise training. These findings suggest that LEA may have negative consequences for skeletal muscle adaptations and highlight the importance of ensuring adequate energy availability in female athletes. Abstract Figure Legend Ten days of low energy availability in trained females performing supervised exercise training resulted in reduced daily integrated myofibrillar and sarcoplasmic muscle protein synthesis compared to optimal energy availability. Concomitant reductions were observed in lean mass, urinary nitrogen balance, free androgen index, thyroid hormone concentrations, and resting metabolic rate following low energy availability. This article is protected by copyright. All rights reserved.

Keywords:  Energy restriction; Female athlete; Menstrual dysfunctions; RED-S

DOI:  https://doi.org/10.1113/JP284967
Proteomics. 2023 Jun 13. e2100314

Proteomic analysis of the small extracellular vesicles and soluble secretory proteins from cachexia inducing and non-inducing cancer cells.

Sai V Chitti, Taeyoung Kang, Pamali Fonseka, Akbar L Marzan, Sarah Stewart, Sanjay Shahi, Kyle Bramich, Ching-Seng Ang, Mohashin Pathan, Sriram Gummadi, Suresh Mathivanan.

  Cancer cachexia is a wasting syndrome characterised by the loss of fat and/or muscle mass in advanced cancer patients. It has been well-established that cancer cells themselves can induce cachexia via the release of several pro-cachectic and pro-inflammatory factors. However, it is unclear how this process is regulated and the key cachexins that are involved. In this study, we validated C26 and EL4 as cachexic and non-cachexic cell models, respectively. Treatment of adipocytes and myotubes with C26 conditioned medium induced lipolysis and atrophy, respectively. We profiled soluble secreted proteins (secretome) as well as small extracellular vesicles (sEVs) released from cachexia-inducing (C26) and non-inducing (EL4) cancer cells by label-free quantitative proteomics. A total of 1268 and 1022 proteins were identified in the secretome of C26 and EL4, respectively. Furthermore, proteomic analysis of sEVs derived from C26 and EL4 cancer cells revealed a distinct difference in the protein cargo. Functional enrichment analysis using FunRich highlighted the enrichment of proteins that are implicated in biological processes such as muscle atrophy, lipolysis, and inflammation in both the secretome and sEVs derived from C26 cancer cells. Overall, our characterisation of the proteomic profiles of the secretory factors and sEVs from cachexia-inducing and non-inducing cancer cells provides insights into tumour factors that promote weight loss by mediating protein and lipid loss in various organs and tissues. Further investigation of these proteins may assist in highlighting potential therapeutic targets and biomarkers of cancer cachexia.

Keywords:  cancer cachexia; lipolysis; muscle atrophy; secretory proteins; small extracellular vesicles

DOI:  https://doi.org/10.1002/pmic.202100314
J Cardiovasc Aging. 2023 ;pii: 25. [Epub ahead of print]3(3):

A worm's life: AMPK links muscle mitochondrial dynamics to physical fitness and healthy aging in Caenorhabditis elegans.

Vihang A Narkar.



Keywords:  AMPK; Exercise; mitochondrial dynamics

DOI:  https://doi.org/10.20517/jca.2023.14
J Biomech. 2023 Jun 05. pii: S0021-9290(23)00238-5. [Epub ahead of print]156 111669

Advances in understanding the energetics of muscle contraction.

C J Barclay, N A Curtin.

  Muscle energetics encompasses the relationships between mechanical performance and the biochemical and thermal changes that occur during muscular activity. The biochemical reactions that underpin contraction are described and the way in which these are manifest in experimental recordings, as initial and recovery heat, is illustrated. Energy use during contraction can be partitioned into that related to cross-bridge force generation and that associated with activation by Ca2+. Activation processes account for 25-45% of ATP turnover in an isometric contraction, varying amongst muscles. Muscle energy use during contraction depends on the nature of the contraction. When shortening muscles produce less force than when contracting isometrically but use energy at a greater rate. These characteristics reflect more rapid cross-bridge cycling when shortening. When lengthening, muscles produce more force than in an isometric contraction but use energy at a lower rate. In that case, cross-bridges cycle but via a pathway in which ATP splitting is not completed. Shortening muscles convert part of the free energy available from ATP hydrolysis into work with the remainder appearing as heat. In the most efficient muscle studied, that of a tortoise, cross-bridges convert a maximum of 47% of the available energy into work. In most other muscles, only 20-30% of the free energy from ATP hydrolysis is converted into work.

Keywords:  Muscle; Muscle energetics; Muscle heat production; Muscle mechanics; Skeletal muscle

DOI:  https://doi.org/10.1016/j.jbiomech.2023.111669
Sci Rep. 2023 Jun 09. 13(1): 9446

GLP‑1 receptor agonist protects palmitate-induced insulin resistance in skeletal muscle cells by up-regulating sestrin2 to promote autophagy.

Xue Tian, Yu Gao, Mowei Kong, Lihua Zhao, Enhong Xing, Qitian Sun, Jianqiu He, Yanan Lu, Zengbin Feng.

In this study, we aimed to determine whether liraglutide could effectively reduce insulin resistance (IR) by regulating Sestrin2 (SESN2) expression in L6 rat skeletal muscle cells by examining its interactions with SESN2, autophagy, and IR. L6 cells were incubated with liraglutide (10-1000 nM) in the presence of palmitate (PA; 0.6 mM), and cell viability was detected using the cell counting kit-8 (CCK-8) assay. IR-related and autophagy-related proteins were detected using western blotting, and IR and autophagy-related genes were analyzed using quantitative real-time polymerase chain reaction. Silencing SESN2 was used to inhibit the activities of SESN2. A reduction in insulin-stimulated glucose uptake was observed in PA-treated L6 cells, confirming IR. Meanwhile, PA decreased the levels of GLUT4 and phosphorylation of Akt and affected SESN2 expression. Further investigation revealed that autophagic activity decreased following PA treatment, but that liraglutide reversed this PA-induced reduction in autophagic activity. Additionally, silencing SESN2 inhibited the ability of liraglutide to up-regulate the expression of IR-related proteins and activate autophagy signals. In summary, the data showed that liraglutide improved PA-induced IR in L6 myotubes by increasing autophagy mediated by SESN2.

DOI: https://doi.org/10.1038/s41598-023-36602-6