## 4 Discussion
This muscle weakness worsens the pain and immobility of patients with OA who already have impaired shock-absorbing properties of the knee joint due to the injured cartilage [33] and malalignment and abnormal loading at the patellofemoral joint [34] to form a vicious cycle, that is, joint pain-decreased movement-muscle weakness-decreased stability of joint-more pain. Although it is clear that changes in skeletal muscles are important players in OA and its symptoms [5; 6; 7; 8; 10; 35; 36; 37], there are few methods to strengthen muscles such as exercise or physical therapy. Additionally, these methods are not always possible for patients to perform due to atrophic muscles and severe joint pain, especially in older people. Furthermore, the degree of benefits of exercise for patients with OA varies widely [38; 39; 40; 41], and inappropriate exercises that may involve excessive mechanical stress on the already injured OA joint are even harmful [35]. Thus, MEST may provide an alternative or complementary approach to overcome the current limitations of exercise and physical therapy for OA management by directly regulating specific skeletal muscles related to the OA joint. When the muscles are stronger, they absorb some of the force that would otherwise go through the joint, help relieve pain, and keep the mechanics of the joint working properly. Given that the architecture and metabolism of skeletal muscles are highly sensitive to the mechanical environment [42], the inserted cog filaments may trigger skeletal muscle plasticity by directly stimulating muscle cells. Mechanical stimuli (e.g., an increase in cell membrane tension through stretching, deformation, or curvature) may not only lead to ion influx through multiple mechanoreceptors expressed on muscle cells to initiate various intracellular signaling pathways [42; 43; 44; 45] but also local production of signaling molecules and growth factors [42; 46; 47] that affect muscle growth, adaptation, and maintenance. For example, it is well known that mechanical stress on muscle cells induces the local release of IGF-1 [42; 48; 49], a key regulator of overall skeletal muscle mass, to initiate the PI3K/AKT/mTOR pathway to promote muscle growth in an autocrine/paracrine manner [49; 50; 51; 52]. IGF-1 can stimulate the local synthesis of collagen [53] which leads to my ofiber hypertrophy [54; 55] for muscle building. It has also been suggested that consuming collagen supplements in combination with exercise further boosted muscle growth and strength in people with age-related muscle mass loss [56]. Thus, the mechano-transduction mechanism [46], by which cells convert mechanical information into biochemical signals that elicit adaptive responses, may explain muscle enhancement (Figure 3) and IGF-1 and collagen levels (Figure 4) using MEST in OA animals. Additional mechanisms might be necessary to explain the rapid onset of pain relief, and motor improvement started a week after MEST (Figure 2). For instance, similar to the suggested working mechanisms of kinesiology taping [57; 58] or unloader brace [59; 60] for OA management, the filaments inserted across the quadriceps could secure surrounding muscles with cogs to support muscle, improve the imbalance of muscle strength, and increase the stability of the knee joint, thereby resulting in less pain and better movement. Taken together, minimally invasive MEST in the quadriceps is safe, rapid, and effective for relieving pain and motor impairment in MIA-induced knee OA animals. This may provide a novel therapeutic strategy for OA symptom management, but not for the direct treatment of OA. Further studies are needed to complement our findings. For examples, combining MEST with other conventional treatments, such as medication, joint injection, or surgery, may be even more effective than existing methods in terms of OA symptom management. It would be also interesting to compare the effects of MEST in different OA animal models [61], as various reasons cause OA in clinical settings.