Upregulation of Akt signaling enhances femoral fracture healing by accelerating atrophic quadriceps recovery

Abstract

Muscle damage and disuse muscular atrophy are detrimental for fracture healing. It has been reported that the Akt signaling pathway plays a role in skeletal muscle hypertrophy and atrophy. The aim of this study was to further investigate whether promoting local muscle function through regulating Akt signaling affects fracture healing. For this purpose, we combined a rat model of short-term atrophy of the quadriceps with a femoral fracture model. In brief, botulinum toxin-A (BTX) were administered locally into the quadriceps one week before femur osteotomy to induce muscle atrophy. For the following weeks after BTX treatment, animals received injection of the Akt activator SC79 (20mg/kg/week) or the Akt inhibitor MK2206 (100mg/kg/week). We found that SC79 significantly accelerated the recovery of quadriceps weight and fiber size after BTX treatment. Moreover, animals that received SC79 injection showed greater bone callus volumes and superior femur mechanical properties. Immunological analysis revealed that the expression levels of the muscle-specific marker myosin heavy chain (MHC) were increased while expression of a negative regulator of muscle mass and function, myostatin, was decreased after SC79 treatment. Furthermore, SC79 increased the mRNA levels of the myogenic regulatory factors MyoD, MRF4 and Myf5 and promoted myotube formation in vitro. Taken together, these findings reveal that SC79 could accelerate the recovery of reversible muscular atrophy induced by BTX and subsequently promote fracture healing through activation of the Akt signaling pathway, which suggests its therapeutic potential in orthopedics.

A PDGFRβ-PI3K signaling axis mediates periosteal cell activation during fracture healing

“…One could even take advantage of the endogenous growth factors that are produced at the fracture site if the injured area is sensitized by a potent Akt activator SC79, bypassing the need for supra-physiologic dose of PDGF. SC79 has been shown to reduce the area of cortical infarct in a rat model of brain ischemia [33], and treatment with SC79 in rats enhanced femoral fracture healing by accelerating atrophic quadriceps recovery [47]. These studies combined indicate a promising future for Akt activators in the context of wound healing.…”

Taurine suppresses ROS-dependent autophagy via activating Akt/mTOR signaling pathway in calcium oxalate crystals-induced renal tubular epithelial cell injury

“…and EG + Tau (Feeding with drinking water containing 0.75% ethylene glycol + Tau 300 mg/kg/d, i.p.). MK-2206 was resuspended in 30% captisol and intraperitoneally injected in rats at a concentration of 90 mg/kg/48h [ 41 ]. Tau was dissolved in stroke-physiological saline solution and intraperitoneally injected in rats at a concentration of 300 mg/kg/d [ 12 ].…”

High bone microarchitecture, strength, and resistance to bone loss in MRL/MpJ mice correlates with activation of different signaling pathways and systemic factors

“…Activation of p38MAPK was reported to be essential for skeletogenesis and bone homeostasis in mice and was shown to be required for hypoxia‐inducible factor‐1 activation and angiogenesis in osteoblasts . P‐AKT upregulation has been shown to enhance femoral fracture healing and helps in promoting cell survival . Therefore, we speculate that the activation of these two pathways may also play a role in the enhanced bone healing of MRL/MpJ mice.…”

“…59 Therefore, we speculate that the activation of these two pathways may also play a role in the enhanced bone healing of MRL/MpJ mice. P38MAPK and pAKT are well-known signaling pathways that are involved in the healing process.…”