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1. Spatial Gradients of Quantitative MRI as Biomarkers for Early Detection of Osteoarthritis: Data From Human Explants and the Osteoarthritis Initiative

   https://doi.org/10.1002/jmri.28471  

   Wilson, Robert L. ; Emery, Nancy C. ; Pierce, David M. ; Neu, Corey P. ( October 2022 , Journal of Magnetic Resonance Imaging)

   Healthy articular cartilage presents structural gradients defined by distinct zonal patterns through the thickness, which may be disrupted in the pathogenesis of several disorders. Analysis of textural patterns using quantitative MRI data may identify structural gradients of healthy or degenerating tissue that correlate with early osteoarthritis (OA).

   To quantify spatial gradients and patterns in MRI data, and to probe new candidate biomarkers for early severity of OA.

   Retrospective study.

   Fourteen volunteers receiving total knee replacement surgery (eight males/two females/four unknown, average age ± standard deviation: 68.1 ± 9.6 years) and 10 patients from the OA Initiative (OAI) with radiographic OA onset (two males/eight females, average age ± standard deviation: 57.7 ± 9.4 years; initial Kellgren‐Lawrence [KL] grade: 0; final KL grade: 3 over the 10‐year study).

   3.0‐T and 14.1‐T, biomechanics‐based displacement‐encoded imaging, fast spin echo, multi‐slice multi‐echoT2mapping.

   We studied structure and strain in cartilage explants from volunteers receiving total knee replacement, or structure in cartilage of OAI patients with progressive OA. We calculated spatial gradients of quantitative MRI measures (eg, T2) normal to the cartilage surface to enhance zonal variations. We compared gradient values against histologically OA severity, conventional relaxometry, and/or KL grades.

   Multiparametric linear regression for evaluation of the relationship between residuals of the mixed effects models and histologically determined OA severity scoring, with a significance threshold atα = 0.05.

   Gradients of individual relaxometry and biomechanics measures significantly correlated with OA severity, outperforming conventional relaxometry and strain metrics. In human explants, analysis of spatial gradients provided the strongest relationship to OA severity (R² = 0.627). Spatial gradients of T2 from OAI data identified variations in radiographic (KL Grade 2) OA severity in single subjects, while conventional T2 alone did not.

   Spatial gradients of quantitative MRI data may improve the predictive power of noninvasive imaging for early‐stage degeneration.

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2. Deletion of Fibroblast growth factor 9 globally and in skeletal muscle results in enlarged tuberosities at sites of deltoid tendon attachments

   https://doi.org/10.1002/dvdy.383  

   Leek, Connor C. ; Soulas, Jaclyn M. ; Bhattacharya, Iman ; Ganji, Elahe ; Locke, Ryan C. ; Smith, Megan C. ; Bhavsar, Jaysheel D. ; Polson, Shawn W. ; Ornitz, David M. ; Killian, Megan L. ( June 2021 , Developmental Dynamics)

   The growth of most bony tuberosities, like the deltoid tuberosity (DT), rely on the transmission of muscle forces at the tendon‐bone attachment during skeletal growth. Tuberosities distribute muscle forces and provide mechanical leverage at attachment sites for joint stability and mobility. The genetic factors that regulate tuberosity growth remain largely unknown. In mouse embryos with global deletion offibroblast growth factor 9(Fgf9), the DT size is notably enlarged. In this study, we explored the tissue‐specific regulation of DT size using both global and targeted deletion ofFgf9.

   We showed that cell hypertrophy and mineralization dynamics of the DT, as well as transcriptional signatures from skeletal muscle but not bone, were influenced by the global loss ofFgf9. Loss ofFgf9during embryonic growth led to increased chondrocyte hypertrophy and reduced cell proliferation at the DT attachment site. This endured hypertrophy and limited proliferation may explain the abnormal mineralization patterns and locally dysregulated expression of markers of endochondral development inFgf9^nullattachments. We then showed that targeted deletion ofFgf9in skeletal muscle leads to postnatal enlargement of the DT.

   Taken together, we discovered thatFgf9may play an influential role in muscle‐bone cross‐talk during embryonic and postnatal development.

    

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3. ATF4‐dependent increase in mitochondrial‐endoplasmic reticulum tethering following OPA1 deletion in skeletal muscle

   https://doi.org/10.1002/jcp.31204  

   Hinton, Jr., Antentor ; Katti, Prasanna ; Mungai, Margaret ; Hall, Duane D. ; Koval, Olha ; Shao, Jianqiang ; Vue, Zer ; Lopez, Edgar Garza ; Rostami, Rahmati ; Neikirk, Kit ; et al ( February 2024 , Journal of Cellular Physiology)

   Mitochondria and endoplasmic reticulum (ER) contact sites (MERCs) are protein‐ and lipid‐enriched hubs that mediate interorganellar communication by contributing to the dynamic transfer of Ca²⁺, lipid, and other metabolites between these organelles. Defective MERCs are associated with cellular oxidative stress, neurodegenerative disease, and cardiac and skeletal muscle pathology via mechanisms that are poorly understood. We previously demonstrated that skeletal muscle‐specific knockdown (KD) of the mitochondrial fusion mediator optic atrophy 1 (OPA1) induced ER stress and correlated with an induction of Mitofusin‐2, a known MERC protein. In the present study, we tested the hypothesis thatOpa1downregulation in skeletal muscle cells alters MERC formation by evaluating multiple myocyte systems, including from mice andDrosophila, and in primary myotubes. Our results revealed that OPA1 deficiency induced tighter and more frequent MERCs in concert with a greater abundance of MERC proteins involved in calcium exchange. Additionally, loss of OPA1 increased the expression of activating transcription factor 4 (ATF4), an integrated stress response (ISR) pathway effector. ReducingAtf4expression prevented the OPA1‐loss‐induced tightening of MERC structures. OPA1 reduction was associated with decreased mitochondrial and sarcoplasmic reticulum, a specialized form of ER, calcium, which was reversed following ATF4 repression. These data suggest that mitochondrial stress, induced by OPA1 deficiency, regulates skeletal muscle MERC formation in an ATF4‐dependent manner.

    

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4. Lipin1 plays complementary roles in myofibre stability and regeneration in dystrophic muscles

   https://doi.org/10.1113/JP284085  

   Jama, Abdulrahman ; Alshudukhi, Abdullah A. ; Burke, Steve ; Dong, Lixin ; Kamau, John Karanja ; Voss, Andrew Alvin ; Ren, Hongmei ( February 2023 , The Journal of Physiology)

   Duchenne muscular dystrophy (DMD) is a severe muscle wasting disorder caused by dystrophin mutations, leading to the loss of sarcolemmal integrity, and resulting in progressive myofibre necrosis and impaired muscle function. Our previous studies suggest that lipin1 is important for skeletal muscle regeneration and myofibre integrity. Additionally, we discovered that mRNA expression levels of lipin1 were significantly reduced in skeletal muscle of DMD patients and the mdx mouse model. To understand the role of lipin1 in dystrophic muscle, we generated dystrophin/lipin1 double knockout (DKO) mice, and compared the limb muscle pathology and function of wild‐type B10, muscle‐specific lipin1 deficient (lipin1^Myf5cKO), mdx and DKO mice. We found that further knockout of lipin1 in dystrophic muscle exhibited a more severe phenotype characterized by increased necroptosis, fibrosis and exacerbated membrane damage in DKO compared to mdx mice. In barium chloride‐induced muscle injury, both lipin1^Myf5cKOand DKO showed prolonged regeneration at day 14 post‐injection, suggesting that lipin1 is critical for muscle regeneration.In situcontractile function assays showed that lipin1 deficiency in dystrophic muscle led to reduced specific force production. Using a cell culture system, we found that lipin1 deficiency led to elevated expression levels of necroptotic markers and medium creatine kinase, which could be a result of sarcolemmal damage. Most importantly, restoration of lipin1 inhibited the elevation of necroptotic markers in differentiated primary lipin1‐deficient myoblasts. Overall, our data suggests that lipin1 plays complementary roles in myofibre stability and muscle function in dystrophic muscles, and overexpression of lipin1 may serve as a potential therapeutic strategy for dystrophic muscles.image

   We identified that lipin1 mRNA expression levels are significantly reduced in skeletal muscles of Duchenne muscular dystrophy patients and mdx mice.

   We found that further depletion of lipin1 in skeletal muscles of mdx mice induces more severe dystrophic phenotypes, including enhanced myofibre sarcolemma damage, muscle necroptosis, inflammation, fibrosis and reduced specific force production.

   Lipin1 deficiency leads to elevated expression levels of necroptotic markers, whereas restoration of lipin1 inhibits their expression.

   Our results suggest that lipin1 is functionally complementary to dystrophin in muscle membrane integrity and muscle regeneration.

    

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5. Clinical importance of changes in magnetic resonance biomarkers for Duchenne muscular dystrophy

   https://doi.org/10.1002/acn3.51933  

   Willcocks, Rebecca J. ; Barnard, Alison M. ; Daniels, Michael J. ; Forbes, Sean C. ; Triplett, William T. ; Brandsema, John F. ; Finanger, Erika L. ; Rooney, William D. ; Kim, Sarah ; Wang, Dah‐Jyuu ; et al ( November 2023 , Annals of Clinical and Translational Neurology)

   Magnetic resonance (MR) measures of muscle quality are highly sensitive to disease progression and predictive of meaningful functional milestones in Duchenne muscular dystrophy (DMD). This investigation aimed to establish the reproducibility, responsiveness to disease progression, and minimum clinically important difference (MCID) for multiple MR biomarkers at different disease stages in DMD using a large natural history dataset.

   Longitudinal MR imaging and spectroscopy outcomes and ambulatory function were measured in 180 individuals with DMD at three sites, including repeated measurements on two separate days (within 1 week) in 111 participants. These data were used to calculate day‐to‐day reproducibility, responsiveness (standardized response mean, SRM), minimum detectable change, and MCID. A survey of experts was also performed.

   MR spectroscopy fat fraction (FF), as well as MR imaging transverse relaxation time (MRI‐T₂), measures performed in multiple leg muscles, and had high reproducibility (Pearson's R > 0.95). Responsiveness to disease progression varied by disease stage across muscles. The average FF from upper and lower leg muscles was highly responsive (SRM > 0.9) in both ambulatory and nonambulatory individuals. MCID estimated from the distribution of scores, by anchoring to function, and via expert opinion was between 0.01 and 0.05 for FF and between 0.8 and 3.7 ms for MRI‐T₂.

   MR measures of FF and MRI T₂are reliable and highly responsive to disease progression. The MCID for MR measures is less than or equal to the typical annualized change. These results confirm the suitability of these measures for use in DMD and potentially other muscular dystrophies.

    

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