Paraspinal myopathy-induced intervertebral disc degeneration and thoracolumbar kyphosis in TSC1mKO mice model—a preliminary study

Hey, Hwee Weng Dennis; Lam, Wing Moon Raymond; Chan, Chloe Xiaoyun; Zhuo, Wen-Hai; Crombie, Elisa Marie; Tan, Tuan Chun; Chen, Way Cherng; Cool, Simon M.; Tsai, Shih Yin

doi:10.1016/j.spinee.2021.09.003

Cited by 9 publications

(6 citation statements)

References 47 publications

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“…By the age of 12 months, Hspa4 -KO mice developed spinal deformity in the form of kyphosis (Fig. 2 D), indicative of paraspinal muscles weakness [ 23 ]. The protein level of HSPA4L and HSPH1, other members of HSP110 family, was not different between WT and Hspa4 -KO muscles ruling out any compensatory upregulation of the studied proteins in the Hspa4 -KO muscles (Fig.…”

Section: Resultsmentioning

confidence: 99%

Heat shock protein A4 ablation leads to skeletal muscle myopathy associated with dysregulated autophagy and induced apoptosis

et al. 2022

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Background Molecular chaperones assist protein folding, facilitate degradation of misfolded polypeptides, and thereby maintain protein homeostasis. Impaired chaperone activity leads to defective protein quality control that is implicated in multiple skeletal muscle diseases. The heat shock protein A4 (HSPA4) acts as a co-chaperone for HSP70. Previously, we showed that Hspa4 deletion causes impaired protein homeostasis in the heart. However, its functional role in skeletal muscle has not been explored. Methods We performed a comparative phenotypic and biochemical analyses of Hspa4 knockout (KO) mice with wild-type (WT) littermates. Results HSPA4 is markedly upregulated in regenerating WT muscle in vivo, and in differentiated myoblasts in vitro. Hspa4-KO mice are marked by growth retardation and increased variability in body weight, accompanied by 35% mortality rates during the peri-weaning period. The surviving Hspa4-KO mice experienced progressive skeletal muscle myopathy, characterized by increased number of muscle fibers with centralized nuclei, heterogeneous myofiber size distribution, inflammatory cell infiltrates and upregulation of embryonic and perinatal myosin heavy chain transcripts. Hspa4-KO muscles demonstrated an accumulation of autophagosome-associated proteins including microtubule associated protein1 light chain 3-II (LC3-II) and p62/sequestosome accompanied by increased number of TUNEL-positive nuclei. Conclusions Our findings underscore the indispensable role of HSPA4 in maintenance of muscle integrity through contribution in skeletal muscle autophagy and apoptosis, which might provide a novel therapeutic strategy for skeletal muscle morbidities.

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Section: Resultsmentioning

confidence: 99%

Heat shock protein A4 ablation leads to skeletal muscle myopathy associated with dysregulated autophagy and induced apoptosis

et al. 2022

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“… 25 ). Previous studies have proposed that kyphotic deformity develops because of postural changes—as a method of conserving energy 26 , while others have suggested that intervertebral disc degeneration, which can lead to a loss of disc height and bone remodelling, could contribute to the onset of deformity 15 , 30 , 31 . Finally, many have hypothesized that paraspinal and spinopelvic muscular dysfunction are causative factors in the development of spinal deformity 14 , 15 , 20 – 23 .…”

Section: Discussionmentioning

confidence: 99%

“…Specific to deformity, Cho et al 25 found that severe paraspinal muscle injury (2-week ischemia) in rats led to a thoracolumbar kyphotic deformity that persisted for the remainder of the study (12 weeks); however, the authors did not quantify the degenerative changes in the muscles. A recent study knocked-out the TSC1 gene in female mice to create a myopathy within the entire skeletal muscle system and revealed that whole body muscle myopathy leads to thoracolumbar kyphotic deformity in 12-month, but not 9-month-old mice when compared to age-matched controls 26 . This study 26 was limited in that the myopathy was not specific to the paraspinal muscles, but rather affected the entire skeletal muscle system, and the quantity of fibrosis and fatty infiltration were not measured, nor were any functional measures performed.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study knocked-out the TSC1 gene in female mice to create a myopathy within the entire skeletal muscle system and revealed that whole body muscle myopathy leads to thoracolumbar kyphotic deformity in 12-month, but not 9-month-old mice when compared to age-matched controls 26 . This study 26 was limited in that the myopathy was not specific to the paraspinal muscles, but rather affected the entire skeletal muscle system, and the quantity of fibrosis and fatty infiltration were not measured, nor were any functional measures performed. Other mouse models with known whole body skeletal muscle weakness (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…However, because of the long progressive time‐course of degenerative spine disorders in humans, and the lack of muscle data at asymptomatic early disease stages, it is unrealistic to obtain such data in humans. Few animal studies have attempted to untangle the relationship between paraspinal muscle pathophysiology and degenerative spinal deformities 25 , 26 . Cho et al 25 found that severe paraspinal muscle injury (2-week ischemia) in rats led to a thoracolumbar kyphotic deformity; however, the authors did not quantify the degenerative changes in the muscles and the mechanism of muscle injury was likely non-physiologic.…”

Section: Introductionmentioning

confidence: 99%

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Glycerol induced paraspinal muscle degeneration leads to hyper-kyphotic spinal deformity in wild-type mice

Noonan,

Buliung,

Briar

et al. 2023

Sci Rep

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Degenerative spinal disorders, including kyphotic deformity, are associated with a range of degenerative characteristics of the paraspinal musculature. It has therefore been hypothesized that paraspinal muscular dysfunction is a causative factor for degenerative spinal deformity; however, experimental studies demonstrating causative relationships are lacking. Male and female mice received either glycerol or saline injections bilaterally along the length of the paraspinal muscles at four timepoints, each separated by 2 weeks. Immediately after sacrifice, micro-CT was performed to measure spinal deformity; paraspinal muscle biopsies were taken to measure active, passive and structural properties; and lumbar spines were fixed for analysis of intervertebral disc (IVD) degeneration. Glycerol-injected mice demonstrated clear signs of paraspinal muscle degeneration and dysfunction: significantly (p < 0.01) greater collagen content, lower density, lower absolute active force, greater passive stiffness compared to saline-injected mice. Further, glycerol-injected mice exhibited spinal deformity: significantly (p < 0.01) greater kyphotic angle than saline-injected mice. Glycerol-injected mice also demonstrated a significantly (p < 0.01) greater IVD degenerative score (although mild) at the upper-most lumbar level compared to saline-injected mice. These findings provide direct evidence that combined morphological (fibrosis) and functional (actively weaker and passively stiffer) alterations to the paraspinal muscles can lead to negative changes and deformity within the thoracolumbar spine.

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Hospital frailty risk score predicts adverse events in spine surgery

et al. 2022

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Purpose The Hospital Frailty Risk Score (HFRS) is derived from routinely collected data and validated as a geriatric risk stratification tool. This study aimed to evaluate the utility of the HFRS as a predictor for postoperative adverse events in spine surgery. Methods In this retrospective analysis of 2042 patients undergoing spine surgery at a university spine center between 2011 and 2019, HFRS was calculated for each patient. Multivariable logistic regression models were used to assess the relationship between the HFRS and postoperative adverse events. Adverse events were compared between patients with high or low frailty risk. Results Patients with intermediate or high frailty risk showed a higher rate of reoperation (19.7% vs. 12.2%, p < 0.01), surgical site infection (3.4% vs. 0.4%, p < 0.001), internal complications (4.1% vs. 1.1%, p < 0.01), Clavien–Dindo IV complications (8.8% vs. 3.4%, p < 0.001) and transfusion (10.9% vs. 1.5%, p < 0.001). Multivariable logistic regression analyses revealed a high HFRS as independent risk factor for reoperation [odds ratio (OR) = 1.1; 95% confidence interval (CI) 1.0–1.2], transfusion (OR = 1.3; 95% CI 1.2–1.4), internal complications (OR = 1.2; 95% CI 1.1–1.3), surgical site infections (OR = 1.3; 95% CI 1.2–1.5) and other complications (OR = 1.3; 95% CI 1.2–1.4). Conclusion The HFRS can predict adverse events and is an easy instrument, fed from routine hospital data. By identifying risk patients at an early stage, the individual patient risk could be minimized, which leads to less complications and lower costs. Level of evidence Level III – retrospective cohort study Trial registration The study was approved by the local ethics committee (20-1821-104) of the University of Regensburg in February 2020.

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Paraspinal myopathy-induced intervertebral disc degeneration and thoracolumbar kyphosis in TSC1mKO mice model—a preliminary study

Cited by 9 publications

References 47 publications

Heat shock protein A4 ablation leads to skeletal muscle myopathy associated with dysregulated autophagy and induced apoptosis

Heat shock protein A4 ablation leads to skeletal muscle myopathy associated with dysregulated autophagy and induced apoptosis

Glycerol induced paraspinal muscle degeneration leads to hyper-kyphotic spinal deformity in wild-type mice

Hospital frailty risk score predicts adverse events in spine surgery

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