More on NNMT Inhibitors as a Basis for Treating Sarcopenia
Sarcopenia is the name given to the characteristic, progressive loss of muscle mass and strength that takes place with aging, eventually giving rise to frailty. Many different contributing mechanisms are thought to play a role in this process: lower protein intake; dysfunction in processing of dietary protein; dysfunction in the neuromuscular junctions connecting the nervous system to muscle fibers and consequent loss of signaling needed to maintain muscle tissue; loss of muscle stem cell activity and thus a reduced supply of new muscle cells; and so forth. As is usually the case, it is a work in progress to firmly connect the observed cell and tissue changes of sarcopenia to the low-level causes of aging, forms of damage such as mitochondrial dysfunction and the accumulation of senescent cells. It is also challenging to understand which of the mechanisms contributing to sarcopenia are most important, and therefore a priority for the development of therapies.
A few years ago researchers demonstrated that inhibiting NNMT in aging mice produced increased muscle mass and strength. This appears to work because NNMT is involved in the age-related loss of function and induction of cellular senescence in muscle stem cells. In today's open access paper, the same researchers report further on their work to develop small molecule NNMT inhibitors as a potential treatment for sarcopenia. In particular they note that NNMT inhibition is additive to the effects of resistance exercise on muscle, which is a promising development.
Human hallmarks of sarcopenia include muscle weakness and a blunted response to exercise. Nicotinamide N-methyltransferase inhibitors (NNMTis) increase strength and promote the regenerative capacity of aged muscle, thus offering a promising treatment for sarcopenia. Since human hallmarks of sarcopenia are recapitulated in aged (24-month-old) mice, we treated mice from 22 to 24 months of age with NNMTi, intensive exercise, or a combination of both, and compared skeletal muscle adaptations, including grip strength, longitudinal running capacity, plantarflexor peak torque, fatigue, and muscle mass, fiber type, cross-sectional area, and intramyocellular lipid (IMCL) content. Exhaustive proteome and metabolome analyses were completed to identify the molecular mechanisms underlying the measured changes in skeletal muscle pathophysiology.
Remarkably, NNMTi-treated aged sedentary mice showed ~ 40% greater grip strength than sedentary controls, while aged exercised mice only showed a 20% increase relative to controls. Importantly, the grip strength improvements resulting from NNMTi treatment and exercise were additive, with NNMTi-treated exercised mice developing a 60% increase in grip strength relative to sedentary controls. NNMTi treatment also promoted quantifiable improvements in IMCL content and, in combination with exercise, significantly increased gastrocnemius fiber cross-sectional area. Detailed skeletal muscle proteome and metabolome analyses revealed unique molecular mechanisms associated with NNMTi treatment and distinct molecular mechanisms and cellular processes arising from a combination of NNMTi and exercise relative to those given a single intervention.
These studies suggest that NNMTi-based drugs, either alone or combined with exercise, will be beneficial in treating sarcopenia and a wide range of age-related myopathies.