Changes in urinary titin N-terminal fragments as a biomarker of exercise-induced muscle damage in the repeated bout effect

ObjectivesMuscle damage symptoms induced by unaccustomed eccentric contraction exercise can be reduced by repeating the experience several times. This phenomenon is termed the repeated bout effect. Although traditional biochemical markers require invasive blood sampling, biochemical measurements have recently been developed that can be non-invasively performed using urinary titin N-terminal fragment (UTF). However, it is unclear whether UTF can reflect the repeated bout effect. Therefore, the aim of the present study was to clarify whether UTF decreased with the repeated bout effect.DesignThis study compared changes in muscle damage markers between bouts of exercise performed for the first and second time.MethodsEight young men performed 30 eccentric exercises of the elbow flexor on the first day of the first week (Bout 1). A second bout of eccentric exercises, same as the first, was performed 2 weeks later, (Bout 2). The dependent variables were muscle soreness (SOR), maximal voluntary isometric contraction (MVIC), range of motion (ROM), creatine kinase (CK), and UTF. All dependent variables were analyzed using two-way analysis of variance.ResultsNo significant difference was observed in workload or peak torque between the first and second exercise bouts. SOR as well as CK and UTF were significantly lower and ROM and MVIC were significantly higher in Bout 2 in comparison to Bout 1.ConclusionsThese results suggest that UTF sensitively reflects the repeated bout effect and exercise-induced muscle damage can be non-invasively measured.     

生物反馈电刺激联合补中益气汤对产妇产后盆底康复效果的影响

目的探讨生物反馈电刺激联合补中益气汤对产妇产后盆底康复效果的影响。方法将56例初产妇按随机数字表法分成对照组与研究组各28例。对照组给予补中益气汤治疗;研究组在对照组基础上联合生物反馈电刺激治疗,两组均治疗6周。观测盆底肌相关电压、盆底肌力、尿失禁率、性生活质量。结果治疗后,两组盆底电位均值均显著升高,研究组高于对照组(P<0.05);治疗后,研究组尿失禁发生率显著降低,且显著低于对照组(P<0.05);研究组Ⅱ、Ⅲ、IV级肌力显著低于对照组(P<0.05);研究组性生活质量高水平显著高于对照组(P<0.05)。结论生物反馈电刺激联合补中益气汤可有效促进产妇产后盆底康复,效果显著优于单独补中益气汤。     

INAUGURAL ARTICLE by a Recently Elected Academy Member:Functional redundancy of type I and type II receptors in the regulation of skeletal muscle growth by myostatin and activin A

Myostatin (MSTN) is a transforming growth factor-β (TGF-β) family member that normally acts to limit muscle growth. The function of MSTN is partially redundant with that of another TGF-β family member, activin A. MSTN and activin A are capable of signaling through a complex of type II and type I receptors. Here, we investigated the roles of two type II receptors (ACVR2 and ACVR2B) and two type I receptors (ALK4 and ALK5) in the regulation of muscle mass by these ligands by genetically targeting these receptors either alone or in combination specifically in myofibers in mice. We show that targeting signaling in myofibers is sufficient to cause significant increases in muscle mass, showing that myofibers are the direct target for signaling by these ligands in the regulation of muscle growth. Moreover, we show that there is functional redundancy between the two type II receptors as well as between the two type I receptors and that all four type II/type I receptor combinations are utilized in vivo. Targeting signaling specifically in myofibers also led to reductions in overall body fat content and improved glucose metabolism in mice fed either regular chow or a high-fat diet, demonstrating that these metabolic effects are the result of enhanced muscling. We observed no effect, however, on either bone density or muscle regeneration in mice in which signaling was targeted in myofibers. The latter finding implies that MSTN likely signals to other cells, such as satellite cells, in addition to myofibers to regulate muscle homeostasis.

Myostatin (MSTN) is a secreted signaling molecule that normally acts to limit skeletal muscle growth (for review, see ref. 1). Mice lacking MSTN exhibit dramatic increases in muscle mass throughout the body, with individual muscles growing to about twice the normal size (2). MSTN appears to play two distinct roles in regulating muscle size, one to regulate the number of muscle fibers that are formed during development and a second to regulate the growth of those fibers postnatally. The sequence of MSTN has been highly conserved through evolution, with the mature MSTN peptide being identical in species as divergent as humans and turkeys (3). The function of MSTN has also been conserved, and targeted or naturally occurring mutations in MSTN have been shown to cause increased muscling in numerous species, including cattle (3–5), sheep (6), dogs (7), rabbits (8), rats (9), swine (10), goats (11), and humans (12). Numerous pharmaceutical and biotechnology companies have developed biologic agents capable of blocking MSTN activity, and these have been tested in clinical trials for a wide range of indications, including Duchenne and facioscapulohumeral muscular dystrophy, inclusion body myositis, muscle atrophy following falls and hip fracture surgery, age-related sarcopenia, Charcot–Marie–Tooth disease, and cachexia due to chronic obstructive pulmonary disease, end-stage kidney disease, and cancer.The finding that certain inhibitors of MSTN signaling can increase muscle mass even in Mstn^−/− mice revealed that the function of MSTN as a negative regulator of muscle mass is partially redundant with at least one other TGF-β family member (13, 14), and subsequent studies have identified activin A as one of these cooperating ligands (15, 16). MSTN and activin A share many key regulatory and signaling components. For example, the activities of both MSTN and activin A can be modulated extracellularly by naturally occurring inhibitory binding proteins, including follistatin (17, 18) and the follistatin-related protein, FSTL-3 or FLRG (19, 20). Moreover, MSTN and activin A also appear to share receptor components. Based on in vitro studies, MSTN is capable of binding initially to the activin type II receptors, ACVR2 and ACVR2B (also called ActRIIA and ActRIIB) (18) followed by engagement of the type I receptors, ALK4 and ALK5 (21). In previous studies, we presented genetic evidence supporting a role for both ACVR2 and ACVR2B in mediating MSTN signaling and regulating muscle mass in vivo. Specifically, we showed that mice expressing a truncated, dominant-negative form of ACVR2B in skeletal muscle (18) or carrying deletion mutations in Acvr2 and/or Acvr2b (13) have significantly increased muscle mass. One limitation of the latter study, however, was that we could not examine the consequence of complete loss of both receptors using the deletion alleles, as double homozygous mutants die early during embryogenesis (22). Moreover, the roles that the two type I receptors, ALK4 and ALK5, play in regulating MSTN and activin A signaling in muscle in vivo have not yet been documented using genetic approaches. Here, we present the results of studies in which we used floxed alleles for each of the type II and type I receptor genes in order to target these receptors alone and in combination in muscle fibers. We show that these receptors are functionally redundant and that signaling through each of these receptors contributes to the overall control of muscle mass.     

Measuring conduction velocity distributions in peripheral nerves using neurophysiological techniques

ObjectiveTo determine how long it takes for neural impulses to travel along peripheral nerve fibers in living humans.MethodsA collision test was performed to measure the conduction velocity distribution of the ulnar nerve. Two stimuli at the distal and proximal sites were used to produce the collision. Compound muscle or nerve action potentials were recorded to perform the measurements on the motor or mixed nerve, respectively. Interstimulus interval was set at 1–5 ms. A quadri-pulse technique was used to measure the refractory period and calibrate the conduction time.ResultsCompound muscle action potential produced by the proximal stimulation started to emerge at the interstimulus interval of about 1.5 ms and increased with the increment in interstimulus interval. Two groups of motor nerve fibers with different conduction velocities were identified. The mixed nerve showed a wider conduction velocity distribution with identification of more subgroups of nerve fibers than the motor nerve.ConclusionsThe conduction velocity distributions in high resolution on a peripheral motor and mixed nerve are different and this can be measured with the collision test.SignificanceWe provided ground truth data to verify the neuroimaging pipelines for the measurements of latency connectome in the peripheral nervous system.     

Notch1 contributes to TNF-α-induced proliferation and migration of airway smooth muscle cells through regulation of the Hes1/PTEN axis

Notch1 has been implicated in asthma pathogenesis. However, the function of Notch1 in regulating airway smooth muscle (ASM) cell proliferation and migration during airway remodeling of asthma remains unknown. Using an in vitro model induced by tumor necrosis factor (TNF)-α, we reported in this study that Notch1 participated in TNF-α-induced proliferation and migration of ASM cells. Our results demonstrated that Notch1 expression was significantly upregulated in ASM cells exposed to TNF-α. Notch1 inhibition significantly repressed TNF-α-induced ASM cell proliferation and migration, while Notch1 overexpression promoted the opposite effect. Moreover, Notch1 inhibition downregulated the expression of Notch-1 intracellular domain (NICD) and Hes1, while upregulated PTEN expression in TNF-α-exposed cells. Notably, Hes1 overexpression partially reversed the Notch1-inhibition-mediated inhibitory effect on TNF-α-induced ASM cell proliferation and migration. In addition, the promoting effect of Notch1 inhibition on PTEN expression was markedly abrogated by Hes1 overexpression. Overall, these findings demonstrated that Notch1 inhibition repressed TNF-α-induced ASM cell proliferation and migration by modulating the Hes1/PTEN signaling axis, a finding that highlights the involvement of Notch1/Hes1/PTEN in regulating airway remodeling of asthma.     

Baseline Sarcopenia is Associated with Lack of Response to Therapy,Liver Decompensation and High Mortality in Hepatocellular Carcinoma Patients

Objective: hepatocellular carcinoma (HCC) is a dreadful complication of liver cirrhosis. Aim was to study the effect of sarcopenia on the survival in patients with HCC. Methods: we included 262 patients and were followed up for 12 months. Sarcopenia was calculated by skeletal muscle index (SMI). Sarcopenia was defined by SMI ≤39 cm2/m2 for women and ≤50 cm2/m2 for men. Results: patients with sarcopenia (n= 113, 43.1%) were older, mainly males, Child-Pugh class B and smokers. Patients with sarcopenia had lower survival than those without (10.09 vs. 11.72 months). Survival was also lower in Barcelona clinic liver cancer stage C than B and A (9.02 vs. 11.21 vs. 11.89 months). Age and sarcopenia were hazardous of mortality (p <0.05). There was statistically significant difference of serial SMI in patients without baseline sarcopenia unlike patients with baseline sarcopenia. On follow up patients with sarcopenia had higher incidence of ascites (45% vs. 20.4%), spontaneous bacterial peritonitis (21.7% vs. 11.6%), hepatic encephalopathy (28% vs. 11.5%) and bleeding (22.9% vs. 12.7%). Totally patients with sarcopenia had higher incidence of progressive HCC (39% vs. 25.5%). Conclusion: Sarcopenia is associated with lack of response to therapy, liver decompensation and higher mortality in hepatocellular carcinoma patients.     

Guideline for Botulinum Toxin Injections in the Effective Treatment of Fibular Spasticity

This study used a modified Sihler's staining method to analyze the nerve distributions of the fibularis muscle to identify the most effective sites for botulinum toxin injection for fibular spasticity treatment. Ten specimens of the fibularis longus and brevis were obtained bilaterally from five fixed cadavers. The applied method of modified Sihler's staining was designed to reveal the intramuscular nerve distribution of the fibularis muscles. We divided the fibularis muscles into four quarters, which were defined as Sections 1–4 starting from the proximal part of the leg. There were one, two, and three nerve entry points in one (10%), six (60%), and three (30%) of the fibularis longus specimens, respectively, and in four (40%), five (50%), and one (10%) of the fibularis brevis specimens, respectively. We counted the number of nerve endings in each section: 321 and 195 points were identified in the fibularis longus and brevis, respectively. The densities of nerve endings were highest in Section 2 of the fibularis longus (147 of 321, 46%) and in Section 3 of the fibularis brevis (78 of 195, 40%). The landmarks used in this study (the fibular head and lateral malleolus) are easily palpable on the skin's surface, allowing clinicians to target the effective injection site (Section 2) without requiring ultrasound guidance, especially for the fibularis longus. Clin. Anat. 33:365–369, 2020. © 2019 Wiley Periodicals, Inc.