Effects of sclerostin injection on soleus and extensor digitorum longus muscle tissue in male mice.

Sclerostin, a potent inhibitor of the Wnt signaling pathway, plays a critical role in bone homeostasis. Evidence suggests that sclerostin may also be involved in crosstalk between other tissues, including muscle. This pilot study attempted to examine the effects of sclerostin on soleus and extensor digitorum longus (EDL) muscle tissue from male mice that were given continuous recombinant sclerostin injections for 4 weeks. A total of 48 10-week-old male C57BL/6J mice were assigned to be sedentary or perform 1 h treadmill running per day for 4 weeks and administered subcutaneous injections of either saline or recombinant sclerostin 5 days/week. Sclerostin injection led to a reduction in the soleus myosin heavy chain (MHC) I, MHC I/IIA, MHC IIA/X, and MHC IIB cross-sectional area (p < 0.05) with no exercise effects on these reductions. In contrast, there were no effects of sclerostin injections or exercise on the fast-twitch EDL muscle in terms of size, MHC protein, or markers of Wnt signaling. These findings provide preliminary evidence of sclerostin's endocrine role in muscle via decreases in myofiber cross-sectional area, which seems to be independent of fiber type but muscle type-specific. More studies, however, are needed to confirm these preliminary results.

Exploring changes in bone mass in individuals with a chronic spinal cord injury.

People experience rapid bone loss shortly after a spinal cord injury (SCI), but the long-term bone changes are yet to be confirmed. This study showed that trabecular bone may have reached a steady state, whereas cortical bone continued to decline in people with a chronic SCI (mean time post injury: 15.5 ± 10 years). INTRODUCTION: (1) To explore changes in bone [primary measure: trabecular volumetric bone mineral density (vBMD); secondary measures: cortical vBMD, cortical thickness, cortical cross-sectional area (CSA), and polar moment of inertia] over 2 years in individuals with a chronic spinal cord injury (SCI). (2) To explore whether muscle density changes were potential correlates of the observed bone changes. METHODS: This study is a secondary data analysis of a prospective, observational study involving 70 people with a chronic SCI (≥ 2 years post injury). The study included 4 strata of participants with diverse impairments: (1) Paraplegia (T1-T12) motor complete American Spinal Injury Association Impairment Scale (AIS) A/B (n = 23), (2) Paraplegia motor incomplete AIS C/D (n = 11), (3) Tetraplegia (C2-C8) AIS A/B (n = 22), and (4) Tetraplegia AIS C/D (n = 14). Peripheral quantitative computed tomography scans were taken at the 4% (distal tibia), 38% (diaphyseal tibia), and 66% (muscle cross-sectional area) tibia sites by measuring from the distal to proximal tibia starting at the inferior border of the medial malleolus. The tibia sites were assessed annually over a span of 2 years. Comparisons were made using a paired-samples t test and simple linear regression was used to adjust for sex, time post injury, and bisphosphonate use. RESULTS: We observed no changes in trabecular vBMD at the 4% tibia site, but there was a statistically significant decline in cortical vBMD, cortical thickness, and CSA at the 38% tibia site. Changes in muscle density were not associated with the decreases observed in cortical bone. CONCLUSION: Our findings suggest that individuals with chronic SCI (mean duration of injury: 15.5 ± 10 years) may have reached a plateau in bone loss with respect to trabecular bone, but cortical bone loss can continue well into the chronic stages.

Changes in bone mass and body composition after bariatric surgery.

Aim: To analyze the effects of body weight loss on bone mineral density (BMD) on hip (Hip BMD) and lumbar spine (Lumbar BMD) after six months of bariatric surgery. Bariatric surgery is an effective treatment for morbid obesity. Nonetheless, there are scant data on the effect of weight bearing on bone structure.Material and methods: Seventeen obese women aged 41.2 ± 11.3 yrs. who underwent Roux-en-Y gastric bypass (RYGB) were included. Body composition assessments were performed through dual-energy X-ray absorptiometry immediately before and after 6-months RYGB. Data collected pre- and post-RYGB included total body weight, body mass index (BMI), lean body mass (LM), fat mass (FM) and bone mineral content. The pre- (PRE) and post-operative (POST) results were compared.Results: Lumbar BMD POST presented a non-significant loss of 1.8% whereas Hip BMD POST showed a significant loss of 17.8%. The analysis demonstrated that BMI and LM PRE explained 26% and 49%, respectively, of Hip BMD PRE variability. In addition, LM POST explained 30% of hip BMD POST variability and was not significant for Lumbar BMD POST.Conclusions: Obesity and rapid weight loss showed direct influence in Hip BMD after six months of bariatric surgery. However, its effect on the lumbar spine area was smaller due to the higher capacity of the spine to dissipate loads through its curvature.

Cortical impairment and reduced muscle mass in children and young adults with nephropathic cystinosis.

Nephropathic cystinosis is an orphan autosomal recessive lysosomal storage disease characterized by a deficiency of cystinosin, a cystine transporter protein, leading to tissue damage, primarily in the kidney and cornea. With the introduction of cystine-depleting therapy with cysteamine and the possibility to survive to adulthood, new challenges of skeletal complications are a concern, with sparse data available regarding bone development. The aim of the current study was to gain more information on bone density and geometry in these patients. Fifty-one patients (29 males, 22 females) with genetically proven nephropathic cystinosis were clinically evaluated with a medical history, physical examination, grip strength measurements, and biochemical and imaging studies. Bone mineral density, bone geometry, and muscle cross sectional area were measured, and muscle was evaluated. Results were compared with age- and gender-specific reference data. Z-scores for height (mean [M] = -1.75, standard deviation [SD] = 1.43), weight (M = -1.67, SD = 1.29), and BMI (M = -0.98, SD = 1.29) were lower than reference data. Medullary cross-sectional area (CSA) and cortical density z-scores were not compromised (M = 0.12, SD = 1.56 and M = -0.25, SD = 1.63, respectively), but cortical CSA z-scores and Strength-Strain Index (SSI) were reduced (M = -2.16, SD = 1.08, M = -2.07, SD = 1.08). Muscular deficits were reflected by reduced z-scores for muscle CSA (M = -2.43, SD = 1.27) and grip strength (M = -3.01, SD = 1.10), along with jump force (34% lower than reference value). Multiple regression analyses indicated an association of muscle mass with medullary CSA and SSI, but not with cortical CSA. While bone density parameters were normal, bone geometry was altered, resulting in a thinner cortex with possible impact on bone strength. Muscle weakness be partially responsible for altered bone geometry and could provide a potential treatment target.

Nephropathic cystinosis is a rare lysosomal storage disease affecting primarily the kidney and cornea. With new treatment options, patients survive to adulthood and challenges such as bone development and fracture risk become a matter of concern. In this study, we investigated bone density, bone geometry, and muscle mass and function using peripheral quantitative-computed tomography. We included 51 patients with genetically proven cystinosis at an age between 6.6 and 39.6 yr. Beside height impairment and low body weight, patients had a thinner bone cortex leading to a reduced stress­strain index. This index represents the resistance of bone against torsional load and, therefore, is considered to be a good marker of bone strength: with low values fracture risk might increase. Furthermore, patients had lower muscle mass and muscle function, the latter evaluated by grip strength and jump force. Looking for the interaction of muscle and bone multiple regression analyses indicated an association of muscle mass with strength strain index. The muscle weakness might be partially responsible for altered bone geometry and lower bone strength and is possibly a treatment target, which has to be investigated in the future.

Bone Geometry Is Altered by Follistatin-Induced Muscle Growth in Young Adult Male Mice.

The development of the musculoskeletal system and its maintenance depends on the reciprocal relationship between muscle and bone. The size of skeletal muscles and the forces generated during muscle contraction are potent sources of mechanical stress on the developing skeleton, and they shape bone structure during growth. This is particularly evident in hypermuscular global myostatin (Mstn)-null mice, where larger muscles during development increase bone mass and alter bone shape. However, whether muscle hypertrophy can similarly influence the shape of bones after the embryonic and prepubertal period is unknown. To address this issue, bone structure was assessed after inducing muscle hypertrophy in the lower hindlimbs of young-adult C57BL/6J male mice by administering intramuscular injections of recombinant adeno-associated viral vectors expressing follistatin (FST), a potent antagonist of Mstn. Two FST isoforms were used: the full-length 315 amino acid isoform (FST-315) and a truncated 288 amino acid isoform (FST-288). In both FST-treated cohorts, muscle hypertrophy was observed, and the anterior crest of the tibia, adjacent to the tibialis anterior muscle, was lengthened. Hypertrophy of the muscles surrounding the tibia caused the adjacent cortical shell to recede inward toward the central axis: an event driven by bone resorption adjacent to the hypertrophic muscle. The findings reveal that inducing muscle hypertrophy in mice can confer changes in bone shape in early adulthood. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Association of serum sclerostin levels with low skeletal muscle mass: The Korean Sarcopenic Obesity Study (KSOS).

BACKGROUND: Sclerostin is an osteocyte-derived circulating protein that inhibits the Wnt/ß-catenin signaling pathway. The Wnt signaling pathway plays an important role in bone and dysregulation of the Wnt signaling pathway results in insulin resistance, inflammation, and metabolic disturbance. The aim of our study was to investigate the implication of sclerostin in low muscle mass in healthy subjects. METHODS: The cross-sectional study analyzed 240 healthy non-diabetic subjects from the Korean Sarcopenic Obesity Study (KSOS). Low muscle mass was defined as the sum of the appendicular skeletal muscle mass divided by the square of height (ASM/height2) as proposed by the Asian Working Group for Sarcopenia. RESULTS: Serum sclerostin was significantly higher in the low muscle mass group than the normal muscle mass group (151.3 [79.2-187.9] vs. 74.8 [47.6-119.6] pg/mL, p = 0.001). In the partial correlation analyses adjusted for age, sex, and body mass index, ASM/height2 was negatively associated with sclerostin levels (r = -0.245, p < 0.001). Furthermore, sclerostin levels decreased linearly according to the first, second, and third tertiles of ASM/height2 even after adjusting for sex, age, body mass index, life style parameters, fasting plasma glucose, bone mineral content (BMC), and total body fat mass. CONCLUSIONS: Serum sclerostin levels were negatively correlated to skeletal muscle mass independent of confounding factors including BMC and total body fat mass.