ERK Inhibition Proposed as a Target for Muscle Regeneration
Many researchers are investigating potential means to spur greater muscle growth and regeneration in older people, ways to at least partially compensate for the characteristic loss of muscle mass and strength that occurs with age, a condition known as sarcopenia. Physical weakness is a sizable component of the frailty of aging, and restoring the ability of the elderly to move and act with confidence would be a tremendous gain. The current range of candidate therapies tend not to address root causes, the underlying molecular damage that causes aging, and vary from the debatable amino acid supplementation to the very promising myostatin blockade. Here researchers propose another possible target and present initial results in mice:
Sarcopenia, age-related loss of muscle quantity and quality, is a crucial determinant of geriatric fragility. Sarcopenia increases susceptibility to muscle damage, serious falls, obesity and diabetes. Age-related changes in muscle are thought to depend on a decrease in muscle stem cells and their niche, which results in global changes in associated gene and protein expression as well as posttranslational modifications. Skeletal muscle regeneration is a multistep process. In response to stimuli generated by exercise or injury, satellite cells re-enter the cell cycle to produce myoblasts, subsequently withdraw from the cell cycle, and differentiate into myocytes, which fuse into new myotubes or with host myofibers. This fusion process is crucial for postnatal growth, maintenance and repair of skeletal muscle in the adult stage. Myotube formation is completely Ca2+ dependent, and requires net Ca2+ influx into myoblasts.
With aging, skeletal muscle shows impaired myogenic potential, which, in turn, induces atrophy. Ca2+ signaling molecules are reported to be associated with age-dependent muscle degeneration. Among the various Ca2+ sensors and channels, inositol 1,4,5-triphosphate receptor type 1 (ITPR1) expression was dramatically decreased in aged muscles and myoblasts. Here, we have provided new evidence that decreased expression of ITPR1 triggers dysregulation of Ca2+ oscillation, which in turn modulate gene expression, resulting in defective myogenesis. Ca2+ oscillation is known to modulate gene expression in many tissues, including muscle.
Multiple studies suggest an important role for the Ras-ERK1/2 pathway in the development, maintenance, and pathology of mammalian skeletal muscle. ERK activity promotes the proliferation of myoblasts and the terminal differentiation of myotubes. We further investigated whether EGFR-Ras-ERK signaling is activated in aged skeletal muscle with decreased ITPR1 expression. Notably, the age-related ITPR1 decline in mice and human skeletal muscles was correlated with increased activation of EGFR-Ras-ERK signaling. To establish whether ERK activation is responsible for inhibition of myogenesis, the ERK pathway was blocked with a specific inhibitor, U0126, in old primary myoblasts. To further evaluate the therapeutic potential of ERK signaling inhibitors for sarcopenia, we examined the effects of U0126 on impaired muscle regeneration in aged mice. U0126 was injected on a daily basis into 6 and 24 month-old C57BL/6 male mice for 13 days after injury. Quantitative real-time PCR data revealed that U0126 induced higher expression of not only myogenic regulatory genes but also those involved in hypertrophy in aged muscle. Consistently, measurements revealed that the newly formed myofibers of U0126-treated muscle had significantly larger diameters than those of controls, supporting the potential of ERK inhibitors as new candidate therapeutic agents for sarcopenia.