Modulating fast skeletal muscle contraction protects skeletal muscle in animal models of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a lethal muscle disease caused by absence of the protein dystrophin, which acts as a structural link between the basal lamina and contractile machinery to stabilize muscle membranes in response to mechanical stress. In DMD, mechanical stress leads to exaggerated membrane injury and fiber breakdown, with fast fibers being the most susceptible to damage. A major contributor to this injury is muscle contraction, controlled by the motor protein myosin. However, how muscle contraction and fast muscle fiber damage contribute to the pathophysiology of DMD has not been well characterized. We explored the role of fast skeletal muscle contraction in DMD with a potentially novel, selective, orally active inhibitor of fast skeletal muscle myosin, EDG-5506. Surprisingly, even modest decreases of contraction (<15%) were sufficient to protect skeletal muscles in dystrophic mdx mice from stress injury. Longer-term treatment also decreased muscle fibrosis in key disease-implicated tissues. Importantly, therapeutic levels of myosin inhibition with EDG-5506 did not detrimentally affect strength or coordination. Finally, in dystrophic dogs, EDG-5506 reversibly reduced circulating muscle injury biomarkers and increased habitual activity. This unexpected biology may represent an important alternative treatment strategy for Duchenne and related myopathies.

Benefits and barriers among volunteer teaching faculty: comparison between those who precept and those who do not in the core pediatrics clerkship.

BACKGROUND: Community-based outpatient experiences are a core component of the clinical years in medical school. Central to the success of this experience is the recruitment and retention of volunteer faculty from the community. Prior studies have identified reasons why some preceptors volunteer their time however, there is a paucity of data comparing those who volunteer from those who do not. METHODS: A survey was developed following a review of previous studies addressing perceptions of community-based preceptors. A non-parametric, Mann-Whitney U test was used to compare active preceptors (APs) and inactive preceptors (IPs) and all data were analyzed in SPSS 20.0. RESULTS: There was a 28% response rate. Preceptors showed similar demographic characteristics, valued intrinsic over extrinsic benefits, and appreciated Continuing Medical Education (CME)/Maintenance of Certification (MOC) opportunities as the highest extrinsic reward. APs were more likely to also precept at the M1/M2 level and value recognition and faculty development opportunities (p<0.05). IPs denoted time as the most significant barrier and, in comparison to APs, rated financial compensation as more important (p<0.05). CONCLUSIONS: Community preceptors are motivated by intrinsic benefits of teaching. Efforts to recruit should initially focus on promoting awareness of teaching opportunities and offering CME/MOC opportunities. Increasing the pool of preceptors may require financial compensation.

Health disparities among highly vulnerable populations in the United States: a call to action for medical and oral health care.

Healthcare in the United States (US) is burdened with enormous healthcare disparities associated with a variety of factors including insurance status, income, and race. Highly vulnerable populations, classified as those with complex medical problems and/or social needs, are one of the fastest growing segments within the US. Over a decade ago, the US Surgeon General publically challenged the nation to realize the importance of oral health and its relationship to general health and well-being, yet oral health disparities continue to plague the US healthcare system. Interprofessional education and teamwork has been demonstrated to improve patient outcomes and provide benefits to participating health professionals. We propose the implementation of interprofessional education and teamwork as a solution to meet the increasing oral and systemic healthcare demands of highly vulnerable US populations.

Plasma matrix metalloproteinase-9 response to eccentric exercise of the elbow flexors.

Recent efforts to establish a role for plasma matrix metalloproteinase-9 (MMP-9) as a marker of exercise-induced muscle damage have been inconsistent. Methodological and experimental design issues have contributed to confusion in this area. The purpose of this study was to use a damaging eccentric arm task to evaluate the relationship between activity-induced muscle damage and plasma MMP-9 levels in humans while controlling for physical activity history and quantifying day-to-day variability of the dependent variables. Fourteen physically inactive males performed 6 sets of 10 eccentric contractions of the elbow flexors at 120% of their voluntary concentric maximum. Soreness ratings, maximum voluntary isometric strength, range of motion (ROM), limb circumference, and plasma creatine kinase (CK) and MMP-9 levels were measured at 2 time points before, immediately after, and 1, 2, 4, and 7 days post-exercise. Changes in traditional markers of muscle damage mirrored patterns previously reported in the literature, but plasma MMP-9 concentration and activity measured by ELISA and gelatin zymography were unchanged at all time points examined. Plasma levels of the MMP-9 inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1), were also unchanged post-exercise. Finally, although mean MMP-9 levels were not significantly different between the two pre-exercise timepoints, the high total error of measurement and low day-to-day correlation suggest substantial within and between subject variability. Plasma MMP-9 levels are not a robust or reliable marker for eccentric exercise-induced damage of the elbow flexor musculature, though this may not preclude a role for MMPs in skeletal muscle remodeling in response to injury.

Acute daily psychological stress causes increased atrophic gene expression and myostatin-dependent muscle atrophy.

Psychological stress is known to attenuate body size and lean body mass. We tested the effects of 1, 3, or 7 days of two different models of psychological stress, 1 h of daily restraint stress (RS) or daily cage-switching stress (CS), on skeletal muscle size and atrophy-associated gene expression in mice. Thymus weights decreased in both RS and CS mice compared with unstressed controls, suggesting that both models activated the hypothalamic-pituitary-adrenal axis. Body mass was significantly decreased at all time points for both models of stress but was greater for RS than CS. Mass of the tibialis anterior (TA) and soleus (SOL) muscles was significantly decreased after 3 and 7 days of RS, but CS only significantly decreased SOL mass after 7 days. TA mRNA levels of the atrophy-associated genes myostatin (MSTN), atrogin-1, and the phosphatidylinositol 3-kinase inhibitory subunit p85alpha were all significantly increased relative to unstressed mice after 1 and 3 days of RS, and expression of MSTN and p85alpha mRNA remained elevated after 7 days of RS. Expression of muscle ring finger 1 was increased after 1 day of RS but returned to baseline at 3 and 7 days of RS. MSTN, atrogin-1, and p85alpha mRNA levels also significantly increased after 1 and 3 days of CS but atrogen-1 mRNA levels had resolved back to normal levels by 3 days and p85alpha with 7 days of CS. p21CIP mRNA levels were significantly decreased by 3 days of CS or RS. Finally, body mass was minimally affected, and muscle mass was completely unaffected by 3 days of RS in mice null for the MSTN gene, and MSTN inactivation attenuated the increase in atrogin-1 mRNA levels with 4 days of RS compared with wild-type mice. Together these data suggest that acute daily psychological stress induces atrophic gene expression and loss of muscle mass that appears to be MSTN dependent.

Myostatin, activin receptor IIb, and follistatin-like-3 gene expression are altered in adipose tissue and skeletal muscle of obese mice.

Myostatin (MSTN) is a secreted growth inhibitor expressed in muscle and adipose. We sought to determine whether expression of MSTN, its receptor activin RIIb (ActRIIb), or its binding protein follistatin-like-3 (FSTL3) are altered in subcutaneous or visceral adipose or in skeletal muscle in response to obesity. MSTN and ActRIIb mRNA levels were low in subcutaneous (SQF) and visceral fat (VF) from wild-type mice but were 50- to 100-fold higher in both SQF and VF from ob/ob compared with wild-type mice. FSTL3 mRNA levels were increased in SQF but decreased in VF in ob/ob compared with wild-type mice. Moreover, MSTN mRNA levels were twofold greater in tibialis anterior (TA) from ob/ob mice, whereas ActRIIb and FSTL3 mRNA levels were unchanged. MSTN mRNA levels were also increased in TA and SQF from mice on a high-fat diet. Injection of ob/ob mice with recombinant leptin caused FSTL3 mRNA levels to decrease in both VF and SQF in ob/ob mice; MSTN and ActRIIb mRNA levels tended to decrease only in VF. Finally, MSTN mRNA levels and promoter activity were low in adipogenic 3T3-L1 cells, but an MSTN promoter-reporter construct was activated in 3T3-L1 cells by cotransfection with the adipogenic transcription factors SREBP-1c, C/EBPalpha, and PPARgamma. These results demonstrate that expression of MSTN and its associated binding proteins can be modulated in adipose tissue and skeletal muscle by chronic obesity and suggest that alterations in their expression may contribute to the changes in growth and metabolism of lean and fat tissues occurring during obesity.