bims-moremu 2024-02-04 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2024‒02‒04
24 papers selected by
Anna Vainshtein, Craft Science Inc.

Human myofiber-enriched aging-induced lncRNA FRAIL1 promotes loss of skeletal muscle function.
The D84G mutation in STIM1 causes nuclear envelope dysfunction and myopathy in mice.
MuSCs and IPCs: roles in skeletal muscle homeostasis, aging and injury.
Mitochondrial involvement in sarcopenia.
Cell-specific functions of androgen receptor in skeletal muscles.
Loss of calpain 3 dysregulates store-operated calcium entry and its exercise response in mice.
Exercise couples mitochondrial function with skeletal muscle fiber type via ROS-mediated epigenetic modification.
Maintenance of the Branched-Chain Amino Acid transporter LAT1 Counteracts Myotube Atrophy following Chemotherapy.
Effects of interleukin-15 on autophagy regulation in the skeletal muscle of mice.
Lifespan effects of muscle-specific androgen receptor overexpression on body composition of male and female rats.
A novel genetic model provides a unique perspective on the relationship between postexercise glycogen concentration and increases in the abundance of key metabolic proteins after acute exercise.
Gene therapy delivered micro-dystrophins co-localize with transgenic utrophin in dystrophic skeletal muscle fibers.
Molecular Effects of Vitamin-D and PUFAs metabolism in Skeletal Muscle combating Type-II Diabetes mellitus.
Kinesin light chain 1 stabilizes insulin receptor substrate 1 to regulate the IGF-1-AKT signaling pathway during myoblast differentiation.
Lentiviral gene therapy with IGF2-tagged GAA normalizes the skeletal muscle proteome in murine Pompe disease.
H2A.Z is involved in premature aging and DSB repair initiation in muscle fibers.
Characterization of CD90/Thy-1 as a crucial molecular signature for myogenic differentiation in human urine-derived cells through single-cell RNA sequencing.
An up-to-date myopathologic characterisation of facioscapulohumeral muscular dystrophy type 1 muscle biopsies shows sarcolemmal complement membrane attack complex deposits and increased skeletal muscle regeneration.
Exploring the links of skeletal muscle mitochondrial oxidative capacity, physical functionality, and mental well-being of cancer survivors.
Uncovering the mechanisms of MuRF1-induced ubiquitylation and revealing similarities with MuRF2 and MuRF3.
Mitochondrial protein C15ORF48 is a stress-independent inducer of autophagy that regulates oxidative stress and autoimmunity.
Matrix-bound nanovesicle-associated IL-33 supports functional recovery after skeletal muscle injury by initiating a pro-regenerative macrophage phenotypic transition.
The serum small non-coding RNA (SncRNA) landscape as a molecular biomarker of age associated muscle dysregulation and insulin resistance in older adults.
Mitochondrial transfer and implications for muscle function in idiopathic inflammatory myopathies.

Aging Cell. 2024 Jan 31. e14097

Human myofiber-enriched aging-induced lncRNA FRAIL1 promotes loss of skeletal muscle function.

Matthew J Miller, Kevin J Gries, George R Marcotte, Zachary Ryan, Matthew D Strub, Hawley E Kunz, Bonnie K Arendt, Surendra Dasari, Scott M Ebert, Christopher M Adams, Ian R Lanza.

  The loss of skeletal muscle mass during aging is a significant health concern linked to adverse outcomes in older individuals. Understanding the molecular basis of age-related muscle loss is crucial for developing strategies to combat this debilitating condition. Long noncoding RNAs (lncRNAs) are a largely uncharacterized class of biomolecules that have been implicated in cellular homeostasis and dysfunction across a many tissues and cell types. To identify lncRNAs that might contribute to skeletal muscle aging, we screened for lncRNAs whose expression was altered in vastus lateralis muscle from older compared to young adults. We identified FRAIL1 as an aging-induced lncRNA with high abundance in human skeletal muscle. In healthy young and older adults, skeletal muscle FRAIL1 was increased with age in conjunction with lower muscle function. Forced expression of FRAIL1 in mouse tibialis anterior muscle elicits a dose-dependent reduction in skeletal muscle fiber size that is independent of changes in muscle fiber type. Furthermore, this reduction in muscle size is dependent on an intact region of FRAIL1 that is highly conserved across non-human primates. Unbiased transcriptional and proteomic profiling of the effects of FRAIL1 expression in mouse skeletal muscle revealed widespread changes in mRNA and protein abundance that recapitulate age-related changes in pathways and processes that are known to be altered in aging skeletal muscle. Taken together, these findings shed light on the intricate molecular mechanisms underlying skeletal muscle aging and implicate FRAIL1 in age-related skeletal muscle phenotypes.

Keywords:  aging; lncRNA; skeletal muscle

DOI:  https://doi.org/10.1111/acel.14097
J Clin Invest. 2024 Feb 01. pii: e170317. [Epub ahead of print]

The D84G mutation in STIM1 causes nuclear envelope dysfunction and myopathy in mice.

Victoria Bryson, Chaojian Wang, Zirui Zhou, Kavisha Singh, Noah M Volin, Eda Yildirim, Paul Rosenberg.

  Stromal interaction molecule 1 (STIM1) is a Ca2+ sensor located in the sarcoplasmic reticulum (SR) of skeletal muscle where it is best known for its role in store operated Ca2+ entry (SOCE). Genetic syndromes resulting from STIM1 mutations are recognized as a cause of muscle weakness and atrophy. Here, we focus on a gain of function mutation that occurs in humans and mice (STIM1+/D84G mice) where muscles exhibit constitutive SOCE. Unexpectedly, this constitutive SOCE did not affect global Ca2+ transients, SR Ca2+ content or excitation contraction coupling (ECC) and was therefore unlikely to underlie the reduced muscle mass and weakness observed in these mice. Instead, we demonstrate that the presence of D84G STIM1 in the nuclear envelope disrupts nuclear-cytosolic coupling causing severe derangement in nuclear architecture of STIM1+/D84G muscle, DNA damage and altered lamina A associated gene expression. Functionally, we found D84G STIM1 reduced the transfer of Ca2+ from the cytosol to the nucleus in myoblasts resulting in a reduction of [Ca2+]N. Taken together, we propose a novel role for STIM1 in the nuclear envelope that links Ca2+ signaling to nuclear stability in skeletal muscle.

Keywords:  Calcium signaling; Cell Biology; Genetic diseases; Muscle Biology

DOI:  https://doi.org/10.1172/JCI170317
Cell Mol Life Sci. 2024 Jan 30. 81(1): 67

MuSCs and IPCs: roles in skeletal muscle homeostasis, aging and injury.

Haiyan Jiang, Boya Liu, Junfei Lin, Tong Xue, Yimin Han, Chunfeng Lu, Songlin Zhou, Yun Gu, Feng Xu, Yuntian Shen, Lingchi Xu, Hualin Sun.

  Skeletal muscle is a highly specialized tissue composed of myofibres that performs crucial functions in movement and metabolism. In response to external stimuli and injuries, a range of stem/progenitor cells, with muscle stem cells or satellite cells (MuSCs) being the predominant cell type, are rapidly activated to repair and regenerate skeletal muscle within weeks. Under normal conditions, MuSCs remain in a quiescent state, but become proliferative and differentiate into new myofibres in response to injury. In addition to MuSCs, some interstitial progenitor cells (IPCs) such as fibro-adipogenic progenitors (FAPs), pericytes, interstitial stem cells expressing PW1 and negative for Pax7 (PICs), muscle side population cells (SPCs), CD133-positive cells and Twist2-positive cells have been identified as playing direct or indirect roles in regenerating muscle tissue. Here, we highlight the heterogeneity, molecular markers, and functional properties of these interstitial progenitor cells, and explore the role of muscle stem/progenitor cells in skeletal muscle homeostasis, aging, and muscle-related diseases. This review provides critical insights for future stem cell therapies aimed at treating muscle-related diseases.

Keywords:  Fibro-adipogenic progenitors; Interstitial progenitor cells; Muscle stem cells; Pericytes; Skeletal muscle

DOI:  https://doi.org/10.1007/s00018-023-05096-w
Acta Physiol (Oxf). 2024 Feb 02. e14107

Mitochondrial involvement in sarcopenia.

Charles Affourtit, Jane E Carré.

  Sarcopenia lowers the quality-of-life for millions of people across the world, as accelerated loss of skeletal muscle mass and function contributes to both age- and disease-related frailty. Physical activity remains the only proven therapy for sarcopenia to date, but alternatives are much sought after to manage this progressive muscle disorder in individuals who are unable to exercise. Mitochondria have been widely implicated in the etiology of sarcopenia and are increasingly suggested as attractive therapeutic targets to help restore the perturbed balance between protein synthesis and breakdown that underpins skeletal muscle atrophy. Reviewing current literature, we note that mitochondrial bioenergetic changes in sarcopenia are generally interpreted as intrinsic dysfunction that renders muscle cells incapable of making sufficient ATP to fuel protein synthesis. Based on the reported mitochondrial effects of therapeutic interventions, however, we argue that the observed bioenergetic changes may instead reflect an adaptation to pathologically decreased energy expenditure in sarcopenic muscle. Discrimination between these mechanistic possibilities will be crucial for improving the management of sarcopenia.

Keywords:  cellular bioenergetics; sarcopenia; skeletal muscle mitochondria

DOI:  https://doi.org/10.1111/apha.14107
Endocr J. 2024 Jan 27.

Cell-specific functions of androgen receptor in skeletal muscles.

Hiroshi Sakai, Yuuki Imai.

  Androgens play a vital role not only in promoting the development of male sexual characteristics but also in exerting diverse physiological effects, including the regulation of skeletal muscle growth and function. Given that the effects of androgens are mediated through androgen receptor (AR) binding, an understanding of AR functionality is crucial for comprehending the mechanisms of androgen action on skeletal muscles. Drawing from insights gained using conditional knockout mouse models facilitated by Cre/loxP technology, we review the cell-specific functions of AR in skeletal muscles. We focus on three specific cell populations expressing AR within skeletal muscles: skeletal muscle cells, responsible for muscle contraction; satellite cells, which are essential stem cells contributing to the growth and regeneration of skeletal muscles; and mesenchymal progenitors, situated in interstitial areas and playing a crucial role in muscle homeostasis. Furthermore, the indirect effects of androgens on skeletal muscle through extra-muscle tissue are essential, especially for the regulation of skeletal muscle mass. The regulation of genes by AR varies across different cell types and contexts, including homeostasis, regeneration and hypertrophy of skeletal muscles. The varied mechanisms orchestrated by AR collectively influence the physiology of skeletal muscles.

Keywords:  Androgen receptor; Mesenchymal progenitors; Myofibers; Satellite cells; Skeletal muscle

DOI:  https://doi.org/10.1507/endocrj.EJ23-0691
bioRxiv. 2024 Jan 15. pii: 2024.01.12.575391. [Epub ahead of print]

Loss of calpain 3 dysregulates store-operated calcium entry and its exercise response in mice.

Katelyn R Villani, Renjia Zhong, C Spencer Henley-Beasley, Giorgia Rastelli, Simona Boncompagni, Elisabeth R Barton, Lan Wei-LaPierre.

Limb-Girdle Muscular Dystrophy 2A (LGMD2A) is caused by mutations in the CAPN3 gene encoding Calpain 3, a skeletal-muscle specific, Ca 2+ -dependent protease. Localization of Calpain 3 within the triad suggests it contributes to Ca 2+ homeostasis. Through live-cell Ca 2+ measurements, muscle mechanics, immunofluorescence, and electron microscopy (EM) in Capn3 deficient (C3KO) and wildtype (WT) mice, we determined if loss of Calpain 3 altered Store-Operated Calcium Entry (SOCE) activity. Direct Ca 2+ influx measurements revealed loss of Capn3 elicits elevated resting SOCE and increased resting cytosolic Ca 2+ , supported by high incidence of calcium entry units (CEUs) observed by EM. C3KO and WT mice were subjected to a single bout of treadmill running to elicit SOCE. Within 1HR post-treadmill running, C3KO mice exhibited diminished force production in extensor digitorum longus muscles and a greater decay of Ca 2+ transients in flexor digitorum brevis muscle fibers during repetitive stimulation. Striking evidence for impaired exercise-induced SOCE activation in C3KO mice included poor colocalization of key SOCE proteins, stromal-interacting molecule 1 (STIM1) and ORAI1, combined with disappearance of CEUs in C3KO muscles. These results demonstrate that Calpain 3 is a key regulator of SOCE in skeletal muscle and identify SOCE dysregulation as a contributing factor to LGMD2A pathology.

DOI: https://doi.org/10.1101/2024.01.12.575391
Free Radic Biol Med. 2024 Jan 29. pii: S0891-5849(24)00044-3. [Epub ahead of print]213 409-425

Exercise couples mitochondrial function with skeletal muscle fiber type via ROS-mediated epigenetic modification.

Jialin Li, Ziyi Zhang, Hai Bo, Yong Zhang.

  Skeletal muscle is a heterogeneous tissue composed of different types of muscle fibers, demonstrating substantial plasticity. Physiological or pathological stimuli can induce transitions in muscle fiber types. However, the precise regulatory mechanisms behind these transitions remains unclear. This paper reviews the classification and characteristics of muscle fibers, along with the classical mechanisms of muscle fiber type transitions. Additionally, the role of exercise-induced muscle fiber type transitions in disease intervention is reviewed. Epigenetic pathways mediate cellular adaptations and thus represent potential targets for regulating muscle fiber type transitions. This paper focuses on the mechanisms by which epigenetic modifications couple mitochondrial function and contraction characteristics. Reactive Oxygen Species (ROS) are critical signaling regulators for the health-promoting effects of exercise. Finally, we discuss the role of exercise-induced ROS in regulating epigenetic modifications and the transition of muscle fiber types.

Keywords:  AMPK; Epigenetic; Exercise; Mitochondria; Muscle fiber type transition; ROS

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.01.036
Am J Physiol Cell Physiol. 2024 Jan 29.

Maintenance of the Branched-Chain Amino Acid transporter LAT1 Counteracts Myotube Atrophy following Chemotherapy.

Stephen Mora, Olasunkanmi A J Adegoke.

  Prevention/management of cachexia remains a critical issue in muscle wasting conditions. The branched-chain amino acids (BCAA) have anabolic properties in skeletal muscle, but their use in treating cachexia has minimal benefits. This may be related to altered BCAA metabolism consequent to the use of chemotherapy, a main cancer treatment. Since this topic is minimally studied, we investigated the effect of chemotherapy on BCAA concentrations, transporter expression and their metabolism. L6 myotubes were treated with vehicle (1.4μL/mL DMSO) or a chemotherapy drug cocktail, folfiri (CPT-11 (20μg/mL), leucovorin (10μg/mL), and 5-fluorouracil (50μg/mL)) for 24 - 48h. Chemotherapy reduced myotube diameter (-43%), myofibrillar protein content (-50%) and phosphorylation of the mTORC1 substrate S6K1thr389 (-80%). Drug-treated myotubes exhibited decreased BCAA concentrations (-50%) and expression of their transporter, LAT1 (-67%). BCAA transaminase BCAT2 level was increased, but there was a reduction in PP2CM (-54%), along with increased inhibitory phosphorylation of BCKDser293 (+98%), corresponding with decreased BCKD enzyme activity (-23%) in chemotherapy-treated myotubes. Decreases in BCAA concentrations were a later response, preceded by decreases in LAT1 and BCKD activity. While supplementation with the BCAA restored myotube BCAA levels, it had minimal effects on preventing the loss of myofibrillar proteins. However, RNAi-mediated depletion of NEdd4, the protein ligase responsible for ubiquitin-dependent degradation of LAT1, attenuated the effects of chemotherapy on BCAA concentrations, anabolic signaling, protein synthesis and myofibrillar protein abundance. Thus, if our findings are validated in preclinical models, interventions regulating muscle amino acid transporters might represent a promising strategy to treat cachexia.

Keywords:  Branched-chain Amino Acids; Cachexia; Chemotherapy; Myotubes

DOI:  https://doi.org/10.1152/ajpcell.00537.2023
Am J Physiol Endocrinol Metab. 2024 Jan 31.

Effects of interleukin-15 on autophagy regulation in the skeletal muscle of mice.

Minoru Tanaka, Ken Sugimoto, Hiroshi Akasaka, Shino Yoshida, Toshimasa Takahashi, Taku Fujimoto, Keyu Xie, Yukiko Yasunobe, Koichi Yamamoto, Takumi Hirabayashi, Ryosuke Nakanishi, Hidemi Fujino, Hiromi Rakugi.

  This study aimed to evaluate the role of skeletal muscle-derived interleukin (IL)-15 in the regulation of skeletal muscle autophagy using IL-15 knockout (KO) and transgenic (TG) mice. Male C57BL/6 wild type (WT), IL-15 KO, and IL-15 TG mice were used in this study. Changes in muscle mass, forelimb grip strength, succinate dehydrogenase (SDH) activity, gene and protein expression levels of major regulators and indicators of autophagy, comprehensive gene expression, and DNA methylation in the gastrocnemius muscle were analyzed. Enrichment pathway analyses revealed that the pathology of IL-15 gene deficiency was related to the autophagosome pathway. Moreover, although IL-15 KO mice maintained gastrocnemius muscle mass, they exhibited a decrease in autophagy induction. IL-15 TG mice exhibited a decrease in gastrocnemius muscle mass and an increase in forelimb grip strength and SDH activity in skeletal muscle. In the gastrocnemius muscle, the ratio of phosphorylated adenosine monophosphate-activated protein kinase α (AMPKα) to total AMPKα and unc-51-like autophagy activating kinase 1 and Beclin1 protein expression were higher in the IL-15 TG group than in the WT group. IL-15 gene deficiency induces a decrease in autophagy induction. In contrast, IL-15 overexpression could improve muscle quality by activating autophagy induction while decreasing muscle mass. The regulation of IL-15 in autophagy in skeletal muscles may lead to the development of therapies for the autophagy-induced regulation of skeletal muscle mass and cellular quality control.

Keywords:  Autophagy; interleukin -15; muscle atrophy; myokine; protein degradation

DOI:  https://doi.org/10.1152/ajpendo.00311.2023
Endocrinology. 2024 Feb 01. pii: bqae012. [Epub ahead of print]

Lifespan effects of muscle-specific androgen receptor overexpression on body composition of male and female rats.

Sabrina Tzivia Barsky, Douglas Ashley Monks.

  Androgenic actions of gonadal testosterone are thought to be a major mechanism promoting sex differences in body composition across the lifespan. However, this inference is based on studies of androgen receptor (AR) function in late adolescent or emerging adult rodents. Here we assess body composition and AR expression in skeletal muscle of rats at defined ages, comparing wild-type (WT) to transgenic HSAAR rats which overexpress AR in skeletal muscle. Male and female HSAAR and WT Sprague Dawley rats (N = 288) underwent DXA scanning and tissue collection at post-natal day (PND) 1, 10, 21, 42, 70, 183, 243, and 365. Expected sex differences in body composition and muscle mass largely onset with puberty (PND-21), with no associated changes to skeletal muscle AR protein. In adulthood, HSAAR increased tibialis anterior (TA) and extensor digitorum longus mass in males, and reduced the expected gain in gonadal fat mass in both sexes. In WT rats, AR protein was reduced in soleus, but not TA, throughout life. Nonetheless, soleus AR protein expression was greater in males than females at all ages of sexual development, yet only at PND-70 in TA. Overall, despite muscle AR overexpression effects, results are inconsistent with major sex differences in body composition during sexual development being driven by changes in muscle AR, rather suggesting that changes in ligand promote sexual differentiation of body composition during pubertal timing. Nonetheless, increased skeletal muscle AR in adulthood can be sufficient to increase muscle mass in males, and reduce adipose in both sexes.

Keywords:  aging; body composition; lifespan; muscle androgen receptor; sex differences

DOI:  https://doi.org/10.1210/endocr/bqae012
PLoS One. 2024 ;19(1): e0295964

A novel genetic model provides a unique perspective on the relationship between postexercise glycogen concentration and increases in the abundance of key metabolic proteins after acute exercise.

Seong Eun Kwak, Amy Zheng, Edward B Arias, Haiyan Wang, Xiufang Pan, Yongping Yue, Dongsheng Duan, Gregory D Cartee.

Some acute exercise effects are influenced by postexercise (PEX) diet, and these diet-effects are attributed to differential glycogen resynthesis. However, this idea is challenging to test rigorously. Therefore, we devised a novel genetic model to modify muscle glycogen synthase 1 (GS1) expression in rat skeletal muscle with an adeno-associated virus (AAV) short hairpin RNA knockdown vector targeting GS1 (shRNA-GS1). Contralateral muscles were injected with scrambled shRNA (shRNA-Scr). Muscles from exercised (2-hour-swim) and time-matched sedentary (Sed) rats were collected immediately postexercise (IPEX), 5-hours-PEX (5hPEX), or 9-hours-PEX (9hPEX). Rats in 5hPEX and 9hPEX experiments were refed (RF) or not-refed (NRF) chow. Muscles were analyzed for glycogen, abundance of metabolic proteins (pyruvate dehydrogenase kinase 4, PDK4; peroxisome proliferator-activated receptor γ coactivator-1α, PGC1α; hexokinase II, HKII; glucose transporter 4, GLUT4), AMP-activated protein kinase phosphorylation (pAMPK), and glycogen metabolism-related enzymes (glycogen phosphorylase, PYGM; glycogen debranching enzyme, AGL; glycogen branching enzyme, GBE1). shRNA-GS1 versus paired shRNA-Scr muscles had markedly lower GS1 abundance. IPEX versus Sed rats had lower glycogen and greater pAMPK, and neither of these IPEX-values differed for shRNA-GS1 versus paired shRNA-Scr muscles. IPEX versus Sed groups did not differ for abundance of metabolic proteins, regardless of GS1 knockdown. Glycogen in RF-rats was lower for shRNA-GS1 versus paired shRNA-Scr muscles at both 5hPEX and 9hPEX. HKII protein abundance was greater for 5hPEX versus Sed groups, regardless of GS1 knockdown or diet, and despite differing glycogen levels. At 9hPEX, shRNA-GS1 versus paired shRNA-Scr muscles had greater PDK4 and PGC1α abundance within each diet group. However, the magnitude of PDK4 or PGC1α changes was similar in each diet group regardless of GS1 knockdown although glycogen differed between paired muscles only in RF-rats. In summary, we established a novel genetic approach to investigate the relationship between muscle glycogen and other exercise effects. Our results suggest that exercise-effects on abundance of several metabolic proteins did not uniformly correspond to differences in postexercise glycogen.

DOI: https://doi.org/10.1371/journal.pone.0295964
Neuromuscul Disord. 2024 Jan 12. pii: S0960-8966(24)00023-3. [Epub ahead of print]36 1-5

Gene therapy delivered micro-dystrophins co-localize with transgenic utrophin in dystrophic skeletal muscle fibers.

Swathy Krishna, Arden B Piepho, Dana M Lake, Laurel R Cumby, Kaelyn K Lortz, Jeovanna Lowe, Jeffrey S Chamberlain, Jill A Rafael-Fortney.

  Duchenne muscular dystrophy (DMD) is a devastating muscle disease caused by the absence of functional dystrophin. There are multiple ongoing clinical trials for DMD that are testing gene therapy treatments consisting of adeno-associated viral (AAV) vectors carrying miniaturized versions of dystrophin optimized for function, termed micro-dystrophins (μDys). Utrophin, the fetal homolog of dystrophin, has repeatedly been reported to be upregulated in human DMD muscle as a compensatory mechanism, but whether µDys displaces full-length utrophin is unknown. In this study, dystrophin/utrophin-deficient mice with transgenic overexpression of full-length utrophin in skeletal muscles were systemically administered low doses of either AAV6-CK8e-Hinge3-µDys (μDysH3) or AAV6-CK8e-μDys5 (μDys5). We used immunofluorescence to qualitatively assess the localization of μDys with transgenic utrophin and neuronal nitric oxide synthase (nNOS) in quadriceps muscles. μDys protein resulting from both gene therapies co-localized at myofiber membranes with transgenic utrophin. We also confirmed the sarcolemmal co-localization of nNOS with μDys5, but not with transgenic utrophin expression or μDysH3. Transgenic utrophin expression and μDys proteins produced from both therapies stabilize the dystrophin-glycoprotein complex as observed by sarcolemmal localization of β-dystroglycan. This study suggests that µDys gene therapy will likely not inhibit any endogenous compensation by utrophin in DMD muscle.

Keywords:  Duchenne muscular dystrophy; Dystrophin; Dystrophin-associated protein complex; Gene therapy; Utrophin

DOI:  https://doi.org/10.1016/j.nmd.2024.01.004
Gene. 2024 Jan 31. pii: S0378-1119(24)00097-0. [Epub ahead of print] 148216

Molecular Effects of Vitamin-D and PUFAs metabolism in Skeletal Muscle combating Type-II Diabetes mellitus.

Rajan Logesh, Balaji Hari, Kumarappan Chidambaram, Niranjan Das.

  Multiple post-receptor intracellular alterations such as impaired glucose transfer, glucose phosphorylation, decreased glucose oxidation, and glycogen production contribute to insulin resistance (IR) in skeletal muscle, manifested by diminished insulin-stimulated glucose uptake. Type-2 diabetes mellites (T2DM) has caused by IR, which is also seen in obese patients and those with metabolic syndrome. The Vitamin-D receptor (VDR) and poly unsaturated fatty acids (PUFAs) roles in skeletal muscle growth, shapes, and function for combating type-2 diabetes have been clarified throughout this research. VDR and PUFAs appears to show a variety of effects on skeletal muscle, in addition it shows a promising role on bone and mineral homeostasis. Individuals having T2DM are reported to suffer from severe muscular weakness and alterations in shape of the muscle. Several studies have investigated the effect on VDR on muscular strength and mass, which leads to Vitamin-D deficiency (VDD) in individuals, in which most commonly seen in elderly. VDR has been shown to affect skeletal cellular proliferation, intracellular calcium handling, as well as genomic activity in a variety of different ways such as muscle metabolism, insulin sensitivity, which is the major characteristic pathogenesis for IR in combating T2DM. The identified VDR gene polymorphisms are ApaI, TaqI, FokI, and BsmI that are associated with T2DM. This review collates informations on the mechanisms by which VDR activation takes place in skeletal muscles. Despite the significant breakthroughs made in recent decades, various studies show that IR affects VDR and PUFAs metabolism in skeletal muscle. Therefore, this review collates the data to show the role of VDR and PUFAs in the skeletal muscles to combat T2DM.

Keywords:  Insulin Resistance; Polyunsaturated Fatty acids; Skeletal muscles; Type 2 Diabetes Mellitus; Vitamin D receptor

DOI:  https://doi.org/10.1016/j.gene.2024.148216
FASEB J. 2024 Feb 15. 38(3): e23432

Kinesin light chain 1 stabilizes insulin receptor substrate 1 to regulate the IGF-1-AKT signaling pathway during myoblast differentiation.

Zihao Qu, Linjing Shi, Zhen Wu, Peng Lin, Guangan Zhang, Xiaoxia Cong, Xiang Zhao, Huiqing Ge, Shigui Yan, Liangjun Jiang, Haobo Wu.

  The IGF signaling pathway plays critical role in regulating skeletal myogenesis. We have demonstrated that KIF5B, the heavy chain of kinesin-1 motor, promotes myoblast differentiation through regulating IGF-p38MAPK activation. However, the roles of the kinesin light chain (Klc) in IGF pathway and myoblast differentiation remain elusive. In this study, we found that Klc1 was upregulated during muscle regeneration and downregulated in senescence mouse muscles and dystrophic muscles from mdx (X-linked muscular dystrophic) mice. Gain- and loss-of-function experiments further displayed that Klc1 promotes AKT-mTOR activity and positively regulates myogenic differentiation. We further identified that the expression levels of IRS1, the critical node of IGF-1 signaling, are downregulated in Klc1-depleted myoblasts. Coimmunoprecipitation study revealed that IRS1 interacted with the 88-154 amino acid sequence of Klc1 via its PTB domain. Notably, the reduced Klc1 levels were found in senescence and osteoporosis skeletal muscle samples from both mice and human. Taken together, our findings suggested a crucial role of Klc1 in the regulation of IGF-AKT pathway during myogenesis through stabilizing IRS1, which might ultimately influence the development of muscle-related disorders.

Keywords:  IGF-1 signaling; insulin receptor substrate-1; kinesin light chain 1; myogenesis; skeletal muscle

DOI:  https://doi.org/10.1096/fj.202201065RR
J Proteomics. 2024 Jan 16. pii: S1874-3919(23)00226-9. [Epub ahead of print]291 105037

Lentiviral gene therapy with IGF2-tagged GAA normalizes the skeletal muscle proteome in murine Pompe disease.

Qiushi Liang, Eva C Vlaar, Joon M Pijnenburg, Erikjan Rijkers, Jeroen A A Demmers, Arnold G Vulto, Ans T van der Ploeg, Niek P van Til, W W M Pim Pijnappel.

  Pompe disease is a lysosomal storage disorder caused by deficiency of acid alpha-glucosidase (GAA), resulting in glycogen accumulation with profound pathology in skeletal muscle. We recently developed an optimized form of lentiviral gene therapy for Pompe disease in which a codon-optimized version of the GAA transgene (LV-GAAco) was fused to an insulin-like growth factor 2 (IGF2) peptide (LV-IGF2.GAAco), to promote cellular uptake via the cation-independent mannose-6-phosphate/IGF2 receptor. Lentiviral gene therapy with LV-IGF2.GAAco showed superior efficacy in heart, skeletal muscle, and brain of Gaa -/- mice compared to gene therapy with untagged LV-GAAco. Here, we used quantitative mass spectrometry using TMT labeling to analyze the muscle proteome and the response to gene therapy in Gaa -/- mice. We found that muscle of Gaa -/- mice displayed altered levels of proteins including those with functions in the CLEAR signaling pathway, autophagy, cytoplasmic glycogen metabolism, calcium homeostasis, redox signaling, mitochondrial function, fatty acid transport, muscle contraction, cytoskeletal organization, phagosome maturation, and inflammation. Gene therapy with LV-GAAco resulted in partial correction of the muscle proteome, while gene therapy with LV-IGF2.GAAco resulted in a near-complete restoration to wild type levels without inducing extra proteomic changes, supporting clinical development of lentiviral gene therapy for Pompe disease. SIGNIFICANCE: Lysosomal glycogen accumulation is the primary cause of Pompe disease, and leads to a cascade of pathological events in cardiac and skeletal muscle and in the central nervous system. In this study, we identified the proteomic changes that are caused by Pompe disease in skeletal muscle of a mouse model. We showed that lentiviral gene therapy with LV-IGF2.GAAco nearly completely corrects disease-associated proteomic changes. This study supports the future clinical development of lentiviral gene therapy with LV-IGF2.GAAco as a new treatment option for Pompe disease.

Keywords:  Acid-alpha glucosidase; Glycogen storage disease type II; Lentiviral gene therapy; Lysosomal storage disease; Pompe disease; Proteome

DOI:  https://doi.org/10.1016/j.jprot.2023.105037
Nucleic Acids Res. 2024 Jan 28. pii: gkae020. [Epub ahead of print]

H2A.Z is involved in premature aging and DSB repair initiation in muscle fibers.

Edwige Belotti, Nicolas Lacoste, Arslan Iftikhar, Thomas Simonet, Christophe Papin, Alexis Osseni, Nathalie Streichenberger, Pierre-Olivier Mari, Emmanuelle Girard, Mohamed Graies, Giuseppina Giglia-Mari, Stefan Dimitrov, Ali Hamiche, Laurent Schaeffer.

Histone variants are key epigenetic players, but their functional and physiological roles remain poorly understood. Here, we show that depletion of the histone variant H2A.Z in mouse skeletal muscle causes oxidative stress, oxidation of proteins, accumulation of DNA damages, and both neuromuscular junction and mitochondria lesions that consequently lead to premature muscle aging and reduced life span. Investigation of the molecular mechanisms involved shows that H2A.Z is required to initiate DNA double strand break repair by recruiting Ku80 at DNA lesions. This is achieved via specific interactions of Ku80 vWA domain with H2A.Z. Taken as a whole, our data reveal that H2A.Z containing nucleosomes act as a molecular platform to bring together the proteins required to initiate and process DNA double strand break repair.

DOI: https://doi.org/10.1093/nar/gkae020
Sci Rep. 2024 01 28. 14(1): 2329

Characterization of CD90/Thy-1 as a crucial molecular signature for myogenic differentiation in human urine-derived cells through single-cell RNA sequencing.

Katsuhiko Kunitake, Norio Motohashi, Takafumi Inoue, Yutaka Suzuki, Yoshitsugu Aoki.

Human urine-derived cells (UDCs) are primary cultured cells originating from the upper urinary tract and are known to be multipotent. We previously developed MYOD1-transduced UDCs (MYOD1-UDCs) as a model recapitulating the pathogenesis of Duchenne muscular dystrophy (DMD) caused by a lack of dystrophin. MYOD1-UDCs also allow evaluation of the efficacy of exon skipping with antisense oligonucleotides. However, despite the introduction of MYOD1, some MYOD1-UDCs failed to form myotubes, possibly because of heterogeneity among UDCs. Here, we carried out single-cell RNA-sequencing analyses and revealed that CD90/Thy-1 was highly expressed in a limited subpopulation of UDCs with high myogenic potency. Furthermore, CD90-positive MYOD1-UDCs, but not CD90-negative cells, could form myotubes expressing high levels of myosin heavy chain and dystrophin. Notably, overexpression of CD90 in CD90-negative MYOD1-UDCs did not enhance myogenic differentiation, whereas CD90 suppression in CD90-positive UDCs led to decreased myotube formation and decreased myosin heavy chain expression. CD90 may thus contribute to the fusion of single-nucleated MYOD1-UDCs into myotubes but is not crucial for promoting the expression of late muscle regulatory factors. Finally, we confirmed that CD90-positive MYOD1-UDCs derived from patients with DMD were a valuable tool for obtaining a highly reproducible and stable evaluation of exon skipping using antisense oligonucleotide.

DOI: https://doi.org/10.1038/s41598-024-52530-5
Neuromuscul Disord. 2024 Jan 14. pii: S0960-8966(24)00002-6. [Epub ahead of print]36 6-15

An up-to-date myopathologic characterisation of facioscapulohumeral muscular dystrophy type 1 muscle biopsies shows sarcolemmal complement membrane attack complex deposits and increased skeletal muscle regeneration.

Lisanne Hubregtse, Karlijn Bouman, Chéryane Lama, Saskia Lassche, Nicolas de Graaf, Valentina Taglietti, Benno Küsters, Baptiste Periou, Frédéric Relaix, Baziel van Engelen, François-Jerôme Authier, Nicol C Voermans, Edoardo Malfatti.

  The aim of this study was to identify key routinely used myopathologic biomarkers of FSHD1. Needle muscle biopsies were taken in 34 affected muscles (m. quadriceps femoris (QF), n = 20, m. tibialis anterior (TA), n = 13, m. biceps brachii, n = 1) from 22 patients (age, 53.5 (10) years; M = 12, F = 10). Eleven patients had more than one biopsy (2xQF, n = 1; QF+TA, n = 9; 2xQF+TA, n = 1). Histochemistry, immunoperoxidase, and immunofluorescence stainings were performed and compared to age and muscle type matched muscle specimens of 11 healthy controls. Myopathologic features observed in our FSHD1 cohort were internalized nuclei, type 1 fibre hypertrophy and NADH central clearances/cores. We observed a prominent inflammatory response with MAC deposits, MHC I expression, and muscle regeneration that correlated with the inflammatory score. Our up-to-date characterization of FSHD1 points towards MHC I, MAC, and embryonic Myosin Heavy Chain/muscle regeneration as useful myopathologic readouts of FSHD1.

Keywords:  Inflammation; Muscle biopsies; Muscular regeneration; Myopathology

DOI:  https://doi.org/10.1016/j.nmd.2024.01.003
Sci Rep. 2024 Feb 01. 14(1): 2669

Exploring the links of skeletal muscle mitochondrial oxidative capacity, physical functionality, and mental well-being of cancer survivors.

Stephen G Gonsalves, Leorey N Saligan, Christopher M Bergeron, Philip R Lee, Kenneth W Fishbein, Richard G Spencer, Marta Zampino, Xinyi Sun, Jennifer Yeong-Shin Sheng, Vered Stearns, Michael Carducci, Luigi Ferrucci, Nada Lukkahatai.

Physical impairments following cancer treatment have been linked with the toxic effects of these treatments on muscle mass and strength, through their deleterious effects on skeletal muscle mitochondrial oxidative capacity. Accordingly, we designed the present study to explore relationships of skeletal muscle mitochondrial oxidative capacity with physical performance and perceived cancer-related psychosocial experiences of cancer survivors. We assessed skeletal muscle mitochondrial oxidative capacity using in vivo phosphorus-31 magnetic resonance spectroscopy (31P MRS), measuring the postexercise phosphocreatine resynthesis time constant, τPCr, in 11 post-chemotherapy participants aged 34-70 years. During the MRS procedure, participants performed rapid ballistic knee extension exercise to deplete phosphocreatine (PCr); hence, measuring the primary study outcome, which was the recovery rate of PCr (τPCr). Patient-reported outcomes of psychosocial symptoms and well-being were assessed using the Patient-Reported Outcomes Measurement Information System and the 36-Item Short Form health survey (SF-36). Rapid bioenergetic recovery, reflected through a smaller value of τPCr was associated with worse depression (rho ρ = - 0.69, p = 0.018, and Cohen's d = - 1.104), anxiety (ρ = - 0.61, p = .046, d = - 0.677), and overall mental health (ρ = 0.74, p = 0.010, d = 2.198) scores, but better resilience (ρ = 0.65, p = 0.029), and coping-self efficacy (ρ = 0.63, p = 0.04) scores. This is the first study to link skeletal muscle mitochondrial oxidative capacity with subjective reports of cancer-related behavioral toxicities. Further investigations are warranted to confirm these findings probing into the role of disease status and personal attributes in these preliminary results.

DOI: https://doi.org/10.1038/s41598-024-52570-x
Biochem Biophys Rep. 2024 Mar;37 101636

Uncovering the mechanisms of MuRF1-induced ubiquitylation and revealing similarities with MuRF2 and MuRF3.

Samuel O Lord, Peter W J Dawson, Jitpisute Chunthorng-Orn, Jimi Ng, Leslie M Baehr, David C Hughes, Pooja Sridhar, Timothy Knowles, Sue C Bodine, Yu-Chiang Lai.

  MuRF1 (Muscle-specific RING finger protein 1; gene name TRIM63) is a ubiquitin E3 ligase, associated with the progression of muscle atrophy. As a RING (Really Interesting New Gene) type E3 ligase, its unique activity of ubiquitylation is driven by a specific interaction with a UBE2 (ubiquitin conjugating enzyme). Our understanding of MuRF1 function remains unclear as candidate UBE2s have not been fully elucidated. In the present study, we screened human ubiquitin dependent UBE2s in vitro and found that MuRF1 engages in ubiquitylation with UBE2D, UBE2E, UBE2N/V families and UBE2W. MuRF1 can cause mono-ubiquitylation, K48- and K63-linked polyubiquitin chains in a UBE2 dependent manner. Moreover, we identified a two-step UBE2 dependent mechanism whereby MuRF1 is monoubiquitylated by UBE2W which acts as an anchor for UBE2N/V to generate polyubiquitin chains. With the in vitro ubiquitylation assay, we also found that MuRF2 and MuRF3 not only share the same UBE2 partners as MuRF1 but can also directly ubiquitylate the same substrates: Titin (A168-A170), Desmin, and MYLPF (Myosin Light Chain, Phosphorylatable, Fast Skeletal Muscle; also called Myosin Light Regulatory Chain 2). In summary, our work presents new insights into the mechanisms that underpin MuRF1 activity and reveals overlap in MuRF-induced ubiquitylation which could explain their partial redundancy in vivo.

Keywords:  Autoubiquitylation; In vitro; Muscle Atrophy; RING E3 Ligase; Ubiquitin; Ubiquitin Conjugating Enzyme (UBE2)

DOI:  https://doi.org/10.1016/j.bbrep.2023.101636
Nat Commun. 2024 Feb 01. 15(1): 953

Mitochondrial protein C15ORF48 is a stress-independent inducer of autophagy that regulates oxidative stress and autoimmunity.

Yuki Takakura, Moeka Machida, Natsumi Terada, Yuka Katsumi, Seika Kawamura, Kenta Horie, Maki Miyauchi, Tatsuya Ishikawa, Nobuko Akiyama, Takao Seki, Takahisa Miyao, Mio Hayama, Rin Endo, Hiroto Ishii, Yuya Maruyama, Naho Hagiwara, Tetsuya J Kobayashi, Naoto Yamaguchi, Hiroyuki Takano, Taishin Akiyama, Noritaka Yamaguchi.

Autophagy is primarily activated by cellular stress, such as starvation or mitochondrial damage. However, stress-independent autophagy is activated by unclear mechanisms in several cell types, such as thymic epithelial cells (TECs). Here we report that the mitochondrial protein, C15ORF48, is a critical inducer of stress-independent autophagy. Mechanistically, C15ORF48 reduces the mitochondrial membrane potential and lowers intracellular ATP levels, thereby activating AMP-activated protein kinase and its downstream Unc-51-like kinase 1. Interestingly, C15ORF48-dependent induction of autophagy upregulates intracellular glutathione levels, promoting cell survival by reducing oxidative stress. Mice deficient in C15orf48 show a reduction in stress-independent autophagy in TECs, but not in typical starvation-induced autophagy in skeletal muscles. Moreover, C15orf48-/- mice develop autoimmunity, which is consistent with the fact that the stress-independent autophagy in TECs is crucial for the thymic self-tolerance. These results suggest that C15ORF48 induces stress-independent autophagy, thereby regulating oxidative stress and self-tolerance.

DOI: https://doi.org/10.1038/s41467-024-45206-1
NPJ Regen Med. 2024 Jan 27. 9(1): 7

Matrix-bound nanovesicle-associated IL-33 supports functional recovery after skeletal muscle injury by initiating a pro-regenerative macrophage phenotypic transition.

J G Bartolacci, M N Behun, J P Warunek, T Li, A Sahu, G K Dwyer, A Lucas, J Rong, F Ambrosio, H R Turnquist, S F Badylak.

Injuries to skeletal muscle are among the most common injuries in civilian and military populations, accounting for nearly 60% of extremity injuries. The standard of care for severe extremity injury has been focused upon limb salvage procedures and the utilization of tissue grafts or orthotics in conjunction with rehabilitation to avoid amputation. Nonetheless, many patients have persistent strength and functional deficits that permanently impact their quality of life. Preclinical and clinical studies have shown that partial restoration of functional skeletal muscle tissue following injury can be achieved by the implantation of a biologic scaffold composed of extracellular matrix (ECM). These favorable outcomes are mediated, at least in part, through local immunomodulation. The mechanisms underlying this immunomodulatory effect, however, are poorly understood. The present study investigates a potential mechanistic driver of the immunomodulatory effects; specifically, the effect of selected ECM components upon inflammation resolution and repair. Results show that the host response to skeletal muscle injury is profoundly altered and functional recovery decreased in il33-/- mice compared to age- and sex-matched wildtype counterparts by 14 days post-injury. Results also show that IL-33, contained within matrix-bound nanovesicles (MBV), supports skeletal muscle regeneration by regulating local macrophage activation toward a pro-remodeling phenotype via canonical and non-canonical pathways to improve functional recovery from injury compared to untreated il33-/- counterparts. Taken together, these data suggest that MBV and their associated IL-33 cargo represent a novel homeostatic signaling mechanism that contributes to skeletal muscle repair.

DOI: https://doi.org/10.1038/s41536-024-00346-2
FASEB J. 2024 Feb 15. 38(3): e23423

The serum small non-coding RNA (SncRNA) landscape as a molecular biomarker of age associated muscle dysregulation and insulin resistance in older adults.

Mark A Burton, Elie Antoun, Emma S Garratt, Leo Westbury, Elaine M Dennison, Nicholas C Harvey, Cyrus Cooper, Harnish P Patel, Keith M Godfrey, Karen A Lillycrop.

  Small noncoding RNAs (sncRNAs) are implicated in age-associated pathologies, including sarcopenia and insulin resistance (IR). As potential circulating biomarkers, most studies have focussed on microRNAs (miRNAs), one class of sncRNA. This study characterized the wider circulating sncRNA transcriptome of older individuals and associations with sarcopenia and IR. sncRNA expression including miRNAs, transfer RNAs (tRNAs), tRNA-associated fragments (tRFs), and piwi-interacting RNAs (piRNAs) was measured in serum from 21 healthy and 21 sarcopenic Hertfordshire Sarcopenia Study extension women matched for age (mean 78.9 years) and HOMA2-IR. Associations with age, sarcopenia and HOMA2-IR were examined and predicted gene targets and biological pathways characterized. Of the total sncRNA among healthy controls, piRNAs were most abundant (85.3%), followed by tRNAs (4.1%), miRNAs (2.7%), and tRFs (0.5%). Age was associated (FDR < 0.05) with 2 miRNAs, 58 tRNAs, and 14 tRFs, with chromatin organization, WNT signaling, and response to stress enriched among gene targets. Sarcopenia was nominally associated (p < .05) with 12 tRNAs, 3 tRFs, and 6 piRNAs, with target genes linked to cell proliferation and differentiation such as Notch Receptor 1 (NOTCH1), DISC1 scaffold protein (DISC1), and GLI family zinc finger-2 (GLI2). HOMA2-IR was nominally associated (p<0.05) with 6 miRNAs, 9 tRNAs, 1 tRF, and 19 piRNAs, linked with lysine degradation, circadian rhythm, and fatty acid biosynthesis pathways. These findings identify changes in circulating sncRNA expression in human serum associated with chronological age, sarcopenia, and IR. These may have clinical utility as circulating biomarkers of ageing and age-associated pathologies and provide novel targets for therapeutic intervention.

Keywords:  HOMA2-IR; ageing; epigenetics; insulin resistance; noncoding RNA; sarcopenia; serum

DOI:  https://doi.org/10.1096/fj.202301089RR
Clin Exp Rheumatol. 2024 Jan 25.

Mitochondrial transfer and implications for muscle function in idiopathic inflammatory myopathies.

International Myositis Health and Research Collaborative Alliance (MIHRA) Mitochondria Scientific Working Group

Impairment in cellular bioenergetics as either the cause, consequence, or major contributor of tissue damage has drawn increasing scientific curiosity across aging and chronic health conditions, with mitochondrial dysfunction emerging as a central mechanism in the pathogenesis of a variety of inflammatory and degenerative disorders. Beyond bioenergetics, mitochondria play critical regulatory roles in programmed cell death of dysfunctional/defective cells as well as in metabolite synthesis and metabolic signalling. Further, extra-cellular exposure to fragmentation of injured mitochondria is associated with incitement of systemic and organ-based inflammation. Thus, mitochondrial function has recently drawn intense, spectral scientific interest as an integral component across maladies.In muscle, mitochondrial dysfunction is clinically associated with atrophy and diminished endurance. Direct myo-histopathological evidence characterising loss of mitochondrial integrity as a hallmark of muscle compromise was first noticed in inclusion body myositis (IBM). This was followed by the discovery of multiple deletions in mitochondrial DNA in sarcopenia, IBM, and other inflammatory myopathies, like dermatomyositis. Though fraught with bioethical considerations, the transplant technology of mitochondrial transfer is swiftly gaining prominence in cellular biology and muscle physiology to remediate mitochondrial diminution and dysfunction. Assembling seminal works and recent developments, this review ventures into the rapidly evolving landscape of mitochondrial transfer, focusing on its implications on muscle function, and offers an integrated perspective on the potential roles of mitochondrial transfer and its implications for preserving and restoring muscle health. Presented here is a consolidated viewpoint on mitochondrial transfer in idiopathic inflammatory myopathies.

DOI: https://doi.org/10.55563/clinexprheumatol/5lfq5x