Towards Drugs to Treat Sarcopenia
Here, researchers review present efforts to develop drugs to treat sarcopenia, the age-related loss of muscle mass and strength that occurs in every individual, leading to eventual frailty. As a snapshot of the research and development community, it is representative of efforts across age-related disease generally, in that the primary focus falls on more easily developed options that cannot possibly produce results larger than those resulting from exercise, particular resistance exercise. This is the unfortunate outcome of the present medical regulatory system, in which the costs of regulatory approval are made so high that concerns and incentives surrounding cost outweigh all other goals.
Sarcopenia is a challenging disease for drug development, and there is currently no clinically approved therapeutic. Outcomes in clinical trials depend on functional gains in muscle performance, rather than just increases in mass, while also being well tolerated with low side effects. Sarcopenia is also a complex multifactorial disorder, and the underlying mechanisms are not fully understood. This review focused on pre-clinical drug development for sarcopenia. Due to the lack of approved therapeutics and a large projected market value, there are a large number and variety of different compounds and target pathways/cellular mechanisms under investigation.
A large proportion of current research is focusing on natural compounds and extracts, due to their characterized biological activity and advantages for further drug development. Much research effort is also focusing on the role of non-coding RNAs in sarcopenia progression, which can provide targets for small molecules currently under development for inhibiting non-coding RNA biogenesis. A number of type 2 diabetes drugs, such as SGLT2 inhibitors, DPP-IV inhibitors, and GLP-1 analogs, are also being investigated for their effects on skeletal muscle mass in type 2 diabetes patients and animal models. It will be important to consider whether these drugs can also be effective in the context of pre-diabetes or normoglycemia.
Mitochondria have a pivotal role in maintaining muscle function and are known to become dysfunctional in aging. Mitochondria-targeting drugs also hold great promise for treating sarcopenia and may utilize recent advances in mitochondria drug delivery systems. Drug repositioning strategies are also providing clinically validated candidates with known pharmacokinetics in humans. These previously characterized drugs can also provide new insights into the molecular pathways regulating skeletal muscle atrophy. A wider adoption of cell-based screening systems, based on known master regulatory genes, such as PGC-1α, could accelerate throughput and increase the number of hits for further analysis. Overall, much effort is being focused on identifying drug candidates with promising pre-clinical therapeutic activity in sarcopenia models, which raises the probability of successful drug development for this debilitating and increasingly prevalent disease.