Progress to Exercise Mimicking Pill

Japanese researchers have made progress on an exercise pill. The exercise pill is a drug that mimics the effect of exercise on muscle and bone. They want to provide this for people who are bedridden or otherwise unable to exercise.

LAMZ augments muscle and bone by mimicking calcium signaling to induce PGC-1α. Schematic of LAMZ function in the augmentation of muscle and bone. Exercise increases the calcium concentration in muscle and bone cells, inducing calcium signaling. Under this signaling, PGC-1α and Mef2c are activated and reciprocally drive their expression. Mitochondriogenic, myogenic and osteogenic genes are induced as well, together augmenting the muscle and bone. Thus, LAMZ facilitates the calcium signaling pathway and restores locomotor fitness.

They have established a novel, three–part drug screening system and discovered a locomomimetic drug, LAMZ. LAMZ enhances myogenesis and osteoblastogenesis via stimulation of calcium-PGC-1α signaling. It can be administered by multiple routes and improves both muscle and bone mass, resulting in increased capacity for locomotion. Therefore, LAMZ has potential as a therapeutic drug for patients with impaired locomotion, such as those with sarcopenia and osteoporosis.

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.

Reinforcement of the muscle and bone during exercise coincides with anabolic changes in both muscle and bone (e.g., increase in proliferation and/or differentiation of myocytes and osteoblasts and a decrease of these in osteoclasts). In search of drugs that can be a substitute for exercise, we established a sequential drug screening system, in which the differentiation of three lineages of cells in muscle and bone (myocytes, osteoblasts and osteoclasts) was quantified. First, we developed a novel method for quantifying the proliferation and differentiation of myocytes. Among 296 compounds in a chemical library, eight were found to enhance the proliferation and/or differentiation of C2C12 cells, a myocyte cell line. Compound 17b, an aminoindazole derivative that showed the strongest promotion of myotube formation, enhanced myosin heavy chain expression. This compound increased the expression of Myod1, Myog, Klf5 and Mef2c, transcription factors known to be induced during myogenesis and to increase differentiation

LAMZ ameliorates the frailty of muscle and bone
To determine whether LAMZ has efficacy as a novel therapeutic drug for impaired locomotion, we orally administered the drug to tail suspension model mice, a disuse model associated with unloading, in which both the muscle and bone of the hindlimb become frail.27 Oral administration of LAMZ significantly upregulated Ppargc1a expression in muscle and bone. In mice treated with this drug during tail suspension, there was an increase in the width of the muscle fibers. Micro-CT analysis revealed that LAMZ treatment increased bone mass. A significant increase in osteoblasts and the osteoid surface was observed in these mice. There was no significant difference in the bone formation rate, owing to the increase in bone formation by tail suspension itself. Osteoclastic bone resorption was decreased by LAMZ treatment in these mice. The reduction of the muscle and bone induced by the disuse model was mitigated by LAMZ treatment

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