In a new study published in Bone Research, Japanese researchers established a novel drug screening system and identified a promising compound to treat age-associated muscle and bone frailty [1].
Musculoskeletal system
Muscle health and bone health are tightly interconnected. Various muscular dystrophies are a great example: disease-caused muscle wasting leads to skeletal deformities, which prompts many patients to undergo orthopedic surgeries.
Aging is also characterized by muscle deterioration (sarcopenia) and bone deterioration (osteoporosis), which often co-exist. In both musculoskeletal diseases and aging, exercise is an important measure to prevent further deterioration, but it is hardly a solution on its own.
In this study, the researchers sought to identify drug candidates targeting both age-associated bone and muscle frailty. They note that most drugs are being developed for either one or the other, causing people to take multiple drugs at the same time (polypharmacy). This leads to poor adherence and might also increase the risk of adverse drug interactions.
Candidate screening
First, the researchers established a drug screening system using bone-building cells (osteoblasts), bone-degrading cells (osteoclasts), and muscle cells (myocytes).
It is believed that to be effective in fighting sarcopenia, a drug should promote myocyte production. Meanwhile, osteoporosis is accompanied by a high activity of osteoclasts, causing bone to be resorbed quickly, and a low activity of osteoblasts, causing bone to form slowly. Therefore, a successful drug should restore the balance between these two bone cell types.
An initial screening of 296 compounds using myocytes allowed the researchers to select eight that were the most effective at promoting the proliferation and differentiation of these cells. These eight compounds were then shown to promote osteoblast generation as well. Among these eight, one compound, locamidazole, had the most potent effect on both myocytes and osteoblasts in addition to suppressing the production of osteoclasts, so it was chosen for further experimentation.
In vivo experiments
To assess if locamidazole is effective in live animals, the researchers divided six-week-old male mice one of three substances: locamidazole, a locamidazole analog known as linifanib, or a control emulsion once a day for 14 days. Histological and behavior analysis confirmed the effectiveness of locamidazole for improving muscle and bone health. Mice in the locamidazole group not only ran a longer distance with fewer fatigue-like episodes than control mice, but also demonstrated an improved muscle strength, enlarged muscle fibers, and denser bones. Importantly, linifanib showed a similar effect.
Next, to uncover the molecular mechanism of locamidazole’s action, the researchers performed RNA-seq analysis and found that the locamidazole group expressed mitochondrial genes more strongly than controls. PGC-1α was then shown to be an important mediator of the beneficial effect of locamidazole on mitochondria synthesis. A follow-up series of experiments revealed that, similarly to exercise, locamidazole stimulates calcium influx into the muscle and bone cells, thus inducing the expression of PGC-1α and Mef2c.
In the final set of experiments, the researchers assessed the therapeutic potential of locamidazole using a mouse model of muscle and bone frailty. In this model, the mice are tail-suspended so that their hind limbs do not touch the ground, which leads to muscle and bone wasting due to disuse.
In line with previous experiments, oral locamidazole administration increased muscle fiber width, bone mass and density, and the expression of PGC-1α, thus ameliorating disuse-caused bone and muscle deterioration in mice. Moreover, delivering the drug via injections demonstrated the same effect, providing a proof-of-concept for multiple administration routes for patients with different limitations.
Abstract
Impaired locomotion has been extensively studied worldwide because those afflicted with it have a potential risk of becoming bedridden. Physical exercise at times can be an effective remedy for frailty, but exercise therapy cannot be applied in all clinical cases. Medication is safer than exercise, but there are no drugs that reinforce both muscle and bone when administered alone. Multiple medications increase the risk of adverse events; thus, there is a need for individual drugs targeting both tissues. To this end, we established a novel sequential drug screening system and identified an aminoindazole derivative, locamidazole (LAMZ), which promotes both myogenesis and osteoblastogenesis while suppressing osteoclastogenesis. Administration of this drug enhanced locomotor function, with muscle and bone significantly strengthened. Mechanistically, LAMZ induced Mef2c and PGC-1α in a calcium signaling–dependent manner. As this signaling is activated upon physical exercise, LAMZ mimics physical exercise. Thus, LAMZ is a promising therapeutic drug for locomotor diseases, including sarcopenia and osteoporosis.
Conclusion
This groundbreaking study underlines the importance of targeting multiple cell types and organs to combat age-associated frailty. Using a three-part drug screening system, the researchers identified locamidazole and its analogs as exercise mimetics, which improve both bone and muscle by increasing the synthesis of mitochondria and can be administered via several routes. While a combination of drugs targeting several pathways of aging is among the approaches being actively studied, one drug targeting several pathologies could be a more feasible solution in many cases.
Literature
[1] Ono, T. et al. Simultaneous augmentation of muscle and bone by locomomimetism through calcium-PGC-1α signaling. Bone Res 10, 52 (2022)
