Effect of exercise on bone in poorly controlled type 1 diabetes mediated by the ActRIIB/Smad signaling pathway

Abstract

Myostatin (MSTN) is not only a key negative regulator of skeletal muscle secretion, however is also an endocrine factor that is transmitted to bone. To investigate the effect and possible mechanism of weight-bearing treadmill running on bone with poorly controlled Type 1 diabetes, rats were randomly divided into three groups: Normal control (NC), diabetic mellitus (DM) and diabetic exercise training groups (DM-WTR). The DM-WTR rats were trained with weight-bearing running. The results demonstrated that the levels of serum insulin, body weight, bone mass, muscle mass, grip strength, and serum calcium in the DM-WTR rats were significantly increased, whereas the levels of blood glucose, alkaline phosphatase, and tartrate-resistant acid phosphatase were markedly reduced in the DM-WTR rats compared with the DM rats. Weight-bearing running inhibited streptozocin (STZ)-induced MSTN mRNA and protein expression in the diabetic rats. The mRNA and protein expression levels of activin type IIB receptor and mothers against decapentaplegic homolog 2/3 and its phosphorylation in femur DM-WTR rats were reduced compared with DM rats. In addition, weight-bearing running enhanced the STZ-induced Wnt and β-catenin expression levels and reduced the STZ-induced glycogen synthase kinase (GSK)-3β expression in diabetic rats' femora. In conclusion, the results suggested that weight-bearing running could partially ameliorate STZ-induced femur atrophy via MSTN downregulation, and this may be associated with the inactivation of Activin A Receptor Type 2B/Smad2/3 signaling pathways and the activation of the Wnt/GSK3β/β-catenin signaling pathway. Further studies are needed to verify these conclusions.

The Role of Irisin in Exercise-Mediated Bone Health

“…Poor glycemic control and glycated hemoglobin (HbA1c) are found to be negatively correlated with BMD (Fuusager et al, 2019). Studies of diabetic mellitus rats demonstrate that running exercise increases the irisin level, glycemic control, bone mass and muscle strength, probable due to the activation of the Wnt/β-catenin signaling pathway and decreased systemic inflammatory process (Andrade et al, 2018;Yang et al, 2018;Sadeghipour et al, 2020). Irisin levels are indicated significantly correlated negatively with HbA1c, years of diabetes, and positively associated with better glycemic control and bone health in TD1M children (Kurdiova et al, 2014;Faienza et al, 2018;Gouda et al, 2018).…”

Deciphering Myostatin’s Regulatory, Metabolic, and Developmental Influence in Skeletal Diseases

“…Further, an 8-week treatment with a polyclonal anti-myostatin antibodies protected diet-induced obese rats from diabetes-associated femoral bone microarchitecture and strength degradation ( Tang et al, 2016 ). Lastly, in a rat model of type 1 diabetes mellitus (T1DM), bone mass, muscle mass, and grip strength were substantially lower relative to healthy controls ( Yang et al, 2018 ). A 6-week weight-bearing exercise regimen improved muscle mass and grip strength, but failed to significantly increase bone mass, although serum levels of the bone resorption marker TRAP, and bone formation marker Alpl were lower and higher, respectively ( Yang et al, 2018 ).…”

“…Lastly, in a rat model of type 1 diabetes mellitus (T1DM), bone mass, muscle mass, and grip strength were substantially lower relative to healthy controls ( Yang et al, 2018 ). A 6-week weight-bearing exercise regimen improved muscle mass and grip strength, but failed to significantly increase bone mass, although serum levels of the bone resorption marker TRAP, and bone formation marker Alpl were lower and higher, respectively ( Yang et al, 2018 ). Hindlimb quadriceps muscles had higher mRNA and protein myostatin levels, which were subsequently lowered with weight-bearing running exercise ( Yang et al, 2018 ).…”

“…A 6-week weight-bearing exercise regimen improved muscle mass and grip strength, but failed to significantly increase bone mass, although serum levels of the bone resorption marker TRAP, and bone formation marker Alpl were lower and higher, respectively ( Yang et al, 2018 ). Hindlimb quadriceps muscles had higher mRNA and protein myostatin levels, which were subsequently lowered with weight-bearing running exercise ( Yang et al, 2018 ). mRNA and protein levels of ActRIIB in femurs were higher in T1DM rats vs. controls, although exercise decreased ActRIIB and Smad2/3 expression ( Yang et al, 2018 ).…”

“…Hindlimb quadriceps muscles had higher mRNA and protein myostatin levels, which were subsequently lowered with weight-bearing running exercise ( Yang et al, 2018 ). mRNA and protein levels of ActRIIB in femurs were higher in T1DM rats vs. controls, although exercise decreased ActRIIB and Smad2/3 expression ( Yang et al, 2018 ). These data suggest the ability of weight-bearing exercise to decrease both the expression of myostatin and the components of its canonical signaling pathway as a means to improve the diabetic bone phenotype.…”