Compositions and methods for increasing muscle mass and oxidative metabolism
A compound and alkoxy technology, applied in the medical field, can solve the problem of no cure for muscular dystrophy
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Embodiment 1
[0225] Exercise does not induce proper myofibrillar gene expression in C3KO muscles. Limb-girdle muscular dystrophy type 2A / R1 / D1 (LGMD2A / R1 / D1) is caused by mutations in the gene encoding the nonlysosomal cysteine protease calpain 3 (CAPN3). Muscles from CAPN3-deficient patients and mice had greatly reduced muscle volume; however, unlike muscular dystrophic lesions, their sarcolemma was stable, suggesting that LGMD2A has a different pathogenic mechanism than dystrophic lesions. CAPN3 localizes to several subcellular compartments, including triads, where it is activated by calmodulin and plays an as-yet-undefined role in calcium release. Previous studies by the inventors have shown that muscles from CAPN3 knockout (C3KO) mice do not grow after a single atrophy. Concomitantly, Ca-calmodulin kinase II (CaMKII) signaling is impaired. Although the muscles of exercise-trained WT mice had increased expression of several lentigenes such as Myl2, Mybph, and Ckmt2, the muscles of C...
Embodiment 2
[0227] AMBMP replaces CAMKII signaling to block and treat LGMD2A. Enhanced expression of CaMKII-induced genes represents a novel target of LGMD2A. Compounds that activate these slow genes may have therapeutic potential against LGMD2A / R1 / D1. In addition, these studies identified pathways involved in normal muscle remodeling, for example, promoting post-atrophic growth and promoting oxidative metabolism. Drugs acting on this pathway could be beneficial in many types of muscle conditions such as cancer cachexia, sarcopenia due to aging and prolonged bed rest. As discussed in WO2017 / 208211, previous studies have identified AMBMP (Formula VI) as a drug to replace CAMKII signaling blockade and treat LGMD2A.
[0228] Figure 11showed that AMBMP causes an increase in slow-twitch fiber diameter. Mean cross-sectional area (CSA) measured in muscle cross-sections after staining for fiber type. Both fiber types showed increases, but only slow fibers showed a significant increase in cr...
Embodiment 3
[0234] Bioactivity data for AMBMP analogs 1-6, 17, 18 and 25. The dose-dependent effects of AMBMP analogs 1-6, 17, 18 and 25 on the expression of endogenous myosin light chain-2 (Myl2) in C2C12 cells are shown in Figure 16A middle.
[0235] The effect of 2.5 [mu]M AMBMP analogs 1-6, 8, 17, 21, 25, 38, 39 and 40 on the expression of My12 relative to GAPDH (a housekeeping control gene) in C2C12 cells is shown in Table 1. My12 is a marker of CaMKIIβ activity.
[0236] Table 1: Myl2 expression in C2C12 cells
[0237]
[0238] The ability of AMBMP analog 3 to induce CaMKIIβ activation and My12 gene expression was tested in vivo. Mice were injected intraperitoneally with 10 mg / kg of AMBMP analog 3. Skeletal muscle was collected at 2, 4 and 6 hours post-injection. Mice injected with DMSO were used as a control group. Figure 16B CaMKIIβ activation in mouse skeletal muscle was shown as indicated by phospho-CaMKIIβ (P-CaMKII or P-CaMK) expression assessed by Western blot usin...
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