Browsing by Author "Soslow, Jonathan"

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    The BDNF rs6265 Polymorphism is a Modifier of Cardiomyocyte Contractility and Dilated Cardiomyopathy
    (MDPI, 2020-10-10) Raucci, Frank J.; Singh, Anand Prakash; Soslow, Jonathan; Markham, Larry W.; Zhong, Lin; Aljafar, Wejdan; Lessiohadi, Natasja; Awgulewitsch, Cassandra P.; Umbarkar, Prachi; Zhang, Qinkun; Cannon, Presley L.; Buchowski, Maciej; Roland, Joseph T.; Carrier, Erica J.; Burnette, William B.; Hatzopoulos, Antonis K.; Lal, Hind; Galindo, Cristi L.; Pediatrics, School of Medicine
    Brain-derived neurotrophic factor (BDNF) is a neuronal growth and survival factor that harbors cardioprotective qualities that may attenuate dilated cardiomyopathy. In ~30% of the population, BDNF has a common, nonsynonymous single nucleotide polymorphism rs6265 (Val66Met), which might be correlated with increased risk of cardiovascular events. We previously showed that BDNF correlates with better cardiac function in Duchenne muscular dystrophy (DMD) patients. However, the effect of the Val66Met polymorphism on cardiac function has not been determined. The goal of the current study was to determine the effects of rs6265 on BDNF biomarker suitability and DMD cardiac functions more generally. We assessed cardiovascular and skeletal muscle function in human DMD patients segregated by polymorphic allele. We also compared echocardiographic, electrophysiologic, and cardiomyocyte contractility in C57/BL-6 wild-type mice with rs6265 polymorphism and in mdx/mTR (mDMD) mouse model of DMD. In human DMD patients, plasma BDNF levels had a positive correlation with left ventricular function, opposite to that seen in rs6265 carriers. There was also a substantial decrease in skeletal muscle function in carriers compared to the Val homozygotes. Surprisingly, the opposite was true when cardiac function of DMD carriers and non-carriers were compared. On the other hand, Val66Met wild-type mice had only subtle functional differences at baseline but significantly decreased cardiomyocyte contractility. Our results indicate that the Val66Met polymorphism alters myocyte contractility, conferring worse skeletal muscle function but better cardiac function in DMD patients. Moreover, these results suggest a mechanism for the relative preservation of cardiac tissues compared to skeletal muscle in DMD patients and underscores the complexity of BDNF signaling in response to mechanical workload.
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    Physical Activity Correlates With Skeletal Muscle MRI Findings in Individuals With Duchenne Muscular Dystrophy
    (Wiley, 2025) Tamaroff, Jaclyn; Joy, Nicholas; Damon, Bruce; Markham, Larry W.; Donnelly, Thomas; Su, Karry; Buchowski, Maciej S.; Crum, Kimberly; Slaughter, James C.; Xu, Meng; Burnette, W. Bryan; Soslow, Jonathan; Pediatrics, School of Medicine
    Introduction/aims: Skeletal muscle magnetic resonance imaging (MRI) is a validated noninvasive tool to assess Duchenne muscular dystrophy (DMD) progression. There is interest in finding DMD biomarkers that decrease the burden of clinical trial participation, such as wearable devices. Our aim was to evaluate the relationship between activity, via accelerometry, and skeletal muscle MRI, particularly T2 mapping. Methods: DMD children and young adults completed skeletal muscle MRI and were asked to wear an accelerometer on the dominant wrist for 7 days. MRI data included fat-suppressed transverse relaxation time (T2) mapping of the calves and longitudinal relaxation time (T1) mapping. Activity was assessed as vector magnitudes (VMs) and fraction of time (FOT) in activity groups (sedentary 1 or 2, low 1 or 2, moderate-to-vigorous physical activity (MVPA)). Results: Participants (n = 22; median age 11.4 years, 41% ambulatory) wore the accelerometer for a median of 7 days. Longer T2 in multiple lower extremity muscles was negatively correlated with VMs per minute (tibialis posterior Spearman's rho = -0.68, p < 0.001), even when accounting for age, ambulatory status, or glucocorticoid use. Longer T2 of the tibialis posterior was positively correlated with FOT in sedentary 1 (rho = 0.49, p = 0.02) and negatively correlated with FOT in higher activity levels (low 1 (rho = -0.58, p = 0.004), low 2 (rho = -0.67, p = 0.002), MVPA (rho = -0.7, p < 0.001)). Discussion: In individuals with DMD, longer T2 on skeletal muscle MRI of the calves moderately correlated with lower activity levels indicating the potential use of home accelerometry as a future clinical trial biomarker of skeletal muscle health and progression in DMD.