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.     

Heterogeneity of executive functions among preschool children with psychiatric symptoms

European Child & Adolescent Psychiatry - The aim of the present study was to investigate associations between internalizing and externalizing symptoms and deficits in executive functions (EF)...     

Safety of zygomatic bone harvesting: a prospective study of 32 consecutive patients with simultaneous zygomatic bone grafting and 1-stage implant placement

PURPOSE: The purpose of this prospective study was to evaluate the safety of zygomatic bone harvesting and to determine whether a particulated zygomatic bone graft can be used simultaneously with 1-stage dental implants to reconstruct resorbed edentulous alveolar ridges. MATERIALS AND METHODS: Altogether, 82 dental implants were placed in 32 patients. Particulated bone grafts harvested from the zygomatic process were used in 72 of the implant sites. The volume of bone harvested, intraoperative complications, morbidity, and complications on follow-up visits were recorded. Implant survival was examined prospectively. RESULTS: As a harvest site, the zygoma yielded enough bone to complete the reconstructions in each case. The average zygomatic bone graft volume was 0.90 mL (SD 0.30). Perforation of the maxillary sinus occurred at 11 zygomatic sites. None of these perforations led to postoperative problems. No paresthesias or other complications were noted during follow-up examinations. Mean duration of postoperative swelling was 4.5 days, and patients used pain medication for a mean duration of 4 days. After the mean follow-up period of 26.9 months postplacement, 80 of 82 implants were osseointegrated (survival rate 97.6%). DISCUSSSION: Zygomatic bone is an alternative donor site for bone harvesting with low morbidity. The bone graft yielded is sufficient for use in 2 to 3 implant sites. CONCLUSIONS: The zygoma was a safe intraoral bone harvesting donor site in this patient population. Further, the use of simultaneous particulated zygomatic bone grafts and 1-stage implant placement appears to be an effective procedure.     

Sizes of dental arches and general body growth up to 6 years of age in children with isolated cleft palate.

Development of the dental arches and height and weight at the ages of 3 yr and 6 yr were studied longitudinally in 60 children with isolated cleft palate (CP) and in 50 noncleft (NONC) children. Retrospective comparisons were also made in the CP group with arch size at the age of 0.2 yr and 1.8 yr. Anterior width at 0.2 yr of age was associated with canine width at the age of 3 yr (r = 0.70) and 6 yr (r = 0.60). Change in maxillary posterior width from 3 yr to 6 yr of age was related to the extension of the cleft, so that in the group with total cleft this dimension diminished. Measured in standard deviation scores (SDS), the means of maxillary width at canines and primary second molars in CP children varied from -1.0 to -2.0 and mandibular dimensions from -0.6 to -1.4. Discrepancy in arch depth diminished with age. Body size differed less from normal than the size of the dental arches. At 3 yr of age the height was -0.4 SDS in CP boys and -0.5 SDS in CP girls, but at 6 yr of age only -0.1 SDS in both boys and girls. Correlations between body size and the size of the dental arches were generally low (r less than 0.20) both in CP and NONC children. The small size of the dental arches in CP children does not seem to be merely a reflection of the overall smaller size of CP children.     

Association between dental fear and dental attendance among adults in Finland

OBJECTIVE: Our aim was to evaluate the association between dental attendance and dental fear while considering the simultaneous effects of perceived oral health and treatment need, satisfaction with oral health services, age, gender, marital status, and attained level of education. MATERIAL AND METHODS: The two-stage stratified cluster sample (n=8028) represented Finnish adults aged 30 years and older. The response rate to this nationwide sample was 88%. Dental fear was measured with the question: "How afraid are you of visiting a dentist?" Multiple logistic regression analyses were used to determine the association between dental fear and dental attendance, including the following independent variables: perceived oral health, perceived treatment need, satisfaction with oral health services, age, gender, marital status, and attained level of education. RESULTS: Among all ages, except 30 to 34-year-olds, irregular attenders were more likely to be very afraid of visiting a dentist than regular attenders were. The association was stronger the older the age group. Only age modified the association between dental fear and attendance. Irregular dental attendance can be attributed to high dental fear (etiologic fraction among exposed) in 41% of cases. CONCLUSION: Reducing dental fear would increase the number of regular attenders, especially among older age groups. Individuals for whom oral health services have been provided regularly since childhood seem to continue to use these services regularly despite high dental fear.     

Improving spatial functioning in children with cerebral palsy using computerized and traditional game tasks

Purpose: To examine the effectiveness of combining virtual environment (VE) instruction with additional desk-top tasks, based on the Luria-Vygotsky methodology, for spatial remediation in children having complex motor disabilities restricting movement.

Method: In Experiment 1, from among children attending for residential rehabilitation, an experimental subgroup had additional spatial training using a VE and corresponding desk-top models. All children were tested at the start and end of training, using four spatial tests. In Experiment 2, larger groups of children (pair-matched for initial performance) were given the same training as in Experiment 1, but experimentals received both VE-based training and supporting tasks designed to improve executive functions and verbal regulation of spatial functioning. Assessment involved a wider range of tests than in Experiment 1.

Results: In Experiment 1, both groups showed improvement at retest, but experimentals showed greater improvement. Children beginning with the lowest level of cognitive performance failed to benefit from the additional training. In Experiment 2 the experimental group made significantly greater improvement than controls, irrespective of initial performance level.

Conclusions: VE-based spatial training is effective for children with complex disabilities, particularly when combined with training that remediates cognitive weaknesses.     

Long-term use of probucol in the multifactorial primary prevention of vascular disease

Over 1,200 middle-aged men with no apparent vascular disease participated in a 5-year multifactorial primary prevention trial, in which 612 received dietetic, hygienic and—when indicated—pharmacologic treatment for the following risk factors: hyperlipidemia, hypertension, smoking, obesity and abnormal glucose tolerance. Pharmacologic therapy included hypolipidemic agents (mainly probucol and clofibrate) and antihypertensive drugs (mainly diuretics and β blockers). At the end of the 5 years, results in these men were compared with findings in 610 high risk and 593 low risk control subjects, none of whom had received treatment. Although intervention decreased the mean risk factor status of the treated men by 33%, their 5-year coronary incidence exceeded that of the high risk control subjects (3.1 % vs 1.5%). Stroke incidence, however, was markedly reduced in the treated subjects (0% vs 1.3%). Multivariate analysis showed that the coronary events occurred in patients taking β blockers or clofibrate, while few occurred in those receiving probucol or the diuretics. The decrease in mean serum cholesterol was 15% in men receiving only probucol, and ranged from 0% to 13% in those receiving different drug combinations, including clofibrate plus probucol (11%). Probucol also markedly decreased high density lipoprotein cholesterol levels, especially when combined with clofibrate.

It is possible that adverse drug effects offset the probable benefit of an improved risk profile in the treated men, thereby explaining the greater than expected occurrence of cardiac events in this group. The probucol data, however, suggest that it may not be harmful to lower the high density lipoprotein cholesterol level when there is a significant decrease in total cholesterol as well.