Sex-specific role of myostatin signaling in neonatal muscle growth, denervation atrophy, and neuromuscular contractures

Emmert, Marianne E; Aggarwal, Parul; Shay-Winkler, Kritton; Lee, Se-Jin; Goh, Qingnian; Cornwall, Roger

doi:10.7554/elife.81121

Cited by 5 publications

(25 citation statements)

References 82 publications

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“…Following image photography, the MCN in bilateral forelimbs were dissected and fixed in 4% paraformaldehyde for 5 h, and stored in PBS at 4 °C for immunohistochemical staining. The remaining forelimbs were positioned on cork at 90°elbow flexion, imaged by digital X-ray for humerus length and symmetry of joint positioning between bilateral limbs, and fixed in 10% formalin for 48 h. Bilateral brachialis muscles were subsequently removed, soaked in 25% Lugol solution (#32922; Sigma-Aldrich) overnight, and processed for micro-computed tomography (MicroCT) to assess whole muscle size [13][14][15]22]. Post scanning, muscles were recovered in PBS overnight at 4 °C, and digested in 15% sulfuric acid for 30 min the following day.…”

Section: Tissue Collection/preparationmentioning

confidence: 99%

“…Post scanning, muscles were recovered in PBS overnight at 4 °C, and digested in 15% sulfuric acid for 30 min the following day. Muscle bundles were then isolated and imaged for sarcomeres via differential interference contrast (DIC) microscopy at 409 on a Nikon Ti-E SpectraX widefield microscope [13][14][15]22].…”

Section: Tissue Collection/preparationmentioning

confidence: 99%

“…Micro-computed tomography was performed using a Siemens Inveon PET/SPECT/CT scanner (Siemens Medical Solutions) as previously described [15,22]. Briefly, acquisitions were reconstructed using a Feldkamp algorithm with mouse beam-hardening correction, slight noise reduction, 3D matrix size 1024 9 1024 9 1536, according to manufacturer-provided software.…”

Section: Ex-vivo High Resolution Studiesmentioning

confidence: 99%

“…Humerus lengths were quantified through the AXIOVISION program by measuring the distance between the proximal humerus physis to the distal articular surface on digital radiographs [13][14][15]22]. Brachialis whole muscle measurements were obtained by processing the MicroCT scans into digital imaging and communications in medicine (DICOM) images with FIJI programs [62], and subsequently normalizing to humerus length of the corresponding forelimb [13][14][15]22]. Specifically, whole muscle CSA was quantified in SEGMENTATION EDITOR, whereas muscle volume was processed in 3D VIEWER [63].…”

Section: Morphometricsmentioning

confidence: 99%

“…These contractures severely impede mobility of the affected limb, ultimately resulting in dysfunction and disability [4]. Previous work in animal and clinical studies has revealed that contractures are caused by impaired longitudinal growth of denervated muscles [5][6][7][8][9][10][11][12], which is driven by elevated levels of muscle proteasome activity [13][14][15]. It is thus imperative to decipher mechanistic links between denervation, muscle proteostasis, longitudinal muscle growth, and contractures in order to identify novel avenues for contracture prevention and treatment.…”

Section: Introductionmentioning

confidence: 99%

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The role of sympathetic innervation in neonatal muscle growth and neuromuscular contractures

et al. 2023

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Neonatal brachial plexus injury (NBPI), a leading cause of pediatric upper limb paralysis, results in disabling and incurable muscle contractures that are driven by impaired longitudinal growth of denervated muscles. A rare form of NBPI, which maintains both afferent and sympathetic muscle innervation despite motor denervation, protects against contractures. We have previously ruled out a role for NRG/ErbB signaling, the predominant pathway governing antegrade afferent neuromuscular transmission, in modulating the formation of contractures. Our current study therefore investigated the contributions of sympathetic innervation of skeletal muscle in modulating NBPI‐induced contractures. Through chemical sympathectomy and pharmacologic modification with a β2‐adrenergic agonist, we discovered that sympathetic innervation alone is neither required nor sufficient to modulate contracture formation in neonatal mice. Despite this, sympathetic innervation plays an intriguing sex‐specific role in mediating neonatal muscle growth, as the cross‐sectional area (CSA) and volume of normally innervated male muscles were diminished by ablation of sympathetic neurons and increased by β‐adrenergic stimulation. Intriguingly, the robust alterations in CSA occurred with minimal changes to normal longitudinal muscle growth as determined by sarcomere length. Instead, β‐adrenergic stimulation exacerbated sarcomere overstretch in denervated male muscles, indicating potentially discrete regulation of muscle width and length. Future investigations into the mechanistic underpinnings of these distinct aspects of muscle growth are thus essential for improving clinical outcomes in patients affected by muscle disorders in which both length and width are affected.

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Section: Tissue Collection/preparationmentioning

confidence: 99%

Section: Tissue Collection/preparationmentioning

confidence: 99%

Section: Ex-vivo High Resolution Studiesmentioning

confidence: 99%

Section: Morphometricsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The role of sympathetic innervation in neonatal muscle growth and neuromuscular contractures

et al. 2023

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Heme oxygenase‐1 therapy attenuates muscle atrophy following global brachial plexus avulsion in juvenile rats

Qin,

Rui,

Lao

2023

Muscle and Nerve

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Introduction/AimsBrachial plexus injury can seriously affect distal target muscle function, and long‐term denervation leads to irreversible structural damage. In the present study, we examined the effect of hemin, a heme oxygenase‐1 (HO‐1) inducer, on intrinsic forepaw muscle atrophy induced by pan‐plexus injury in juvenile rats, as well as its underlying mechanism.MethodsA global brachial plexus avulsion (GBPA) model of rat was established, and thirty 6‐wk‐old male rats were randomly divided into five groups: control, GBPA plus scramble small intering RNA (siRNA), GBPA plus scramble siRNA plus hemin, GBPA plus HO‐1 siRNA, and GBPA plus HO‐1 siRNA plus hemin. Hemin (50 mg/kg) was administered intraperitoneally once daily and the siRNA (5 μg) was injected intramuscularly twice a week. Intrinsic forepaw muscles were used for analysis. Myofiber cross‐sectional area (CSA), capillary‐to‐fiber ratio (C/F), and fiber‐type composition were assessed. The levels of inflammatory factors, ubiquitin‐protein ligases, and autophagy‐related proteins were also measured.ResultsWe found that hemin treatment could effectively ameliorate denervated intrinsic forepaw muscle atrophy and suppress type I to II myofiber‐type conversion. Hemin treatment failed to prevent muscle capillary loss after denervation. The levels of inflammatory factors (tumor necrosis factor alpha [TNFα] and interleukin 6 [IL‐6]), ubiquitin‐protein ligases (MuRF‐1 and MAFbx), and autophagy‐related proteins (BNIP3 and LC3B‐II/I ratio) were increased by denervation and HO‐1 therapy attenuated the increment.DiscussionUpregulation of HO‐1 might potentially be an effective strategy to alleviate denervation‐related muscle atrophy and might be a promising adjunctive treatment to improve hand function in children with pan‐plexus injury.

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The Role of Sympathetic Innervation in Neonatal Muscle Growth and Neuromuscular Contractures

Runkel

Tarabishi

Shay-Winkler

et al. 2023

Preprint

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Neonatal brachial plexus injury (NBPI), a leading cause of pediatric upper limb paralysis, results in disabling and incurable muscle contractures that are driven by impaired longitudinal growth of denervated muscles. A rare form of NBPI, which maintains both afferent and sympathetic muscle innervation despite motor denervation, protects against contractures. We have previously ruled out a role for NRG/ErbB signaling, the predominant pathway governing antegrade afferent neuromuscular transmission, in modulating the formation of contractures. Our current study therefore investigated the contributions of sympathetic innervation of skeletal muscle in modulating NBPI-induced contractures. Through chemical sympathectomy and pharmacologic modification with a β2-adrenergic agonist, we discovered that sympathetic innervation alone is neither required nor sufficient to modulate contracture formation in neonatal mice. Despite this, sympathetic innervation plays an intriguing sex-specific role in mediating neonatal muscle growth, as the cross-sectional area (CSA) and volume of normally innervated male muscles were diminished by ablation of sympathetic neurons and increased by β-adrenergic stimulation. Intriguingly, the robust alterations in CSA occurred with minimal changes to normal longitudinal muscle growth as determined by sarcomere length. Instead, β-adrenergic stimulation exacerbated sarcomere overstretch in denervated male muscles, indicating potentially discrete regulation of muscle width and length. Future investigations into the mechanistic underpinnings of these distinct aspects of muscle growth are thus essential for improving clinical outcomes in patients affected by muscle disorders in which both length and width are affected.

show abstract

Sex-specific role of myostatin signaling in neonatal muscle growth, denervation atrophy, and neuromuscular contractures

Cited by 5 publications

References 82 publications

The role of sympathetic innervation in neonatal muscle growth and neuromuscular contractures

The role of sympathetic innervation in neonatal muscle growth and neuromuscular contractures

Heme oxygenase‐1 therapy attenuates muscle atrophy following global brachial plexus avulsion in juvenile rats

The Role of Sympathetic Innervation in Neonatal Muscle Growth and Neuromuscular Contractures

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