Are we underestimating the potential of neuroactive drugs to augment neuromotor function in sarcopenia?

Sarcopenia is a skeletal muscle disease characterised by exacerbated loss of muscle mass, strength, and/or impaired function with aging and/or disease [[2], [3], [4], [5], [6], [7]]. Historically, the term “sarcopenia” stems from the Greek words ‘sarx’, for ‘flesh’, and ‘penia’, for ‘loss’, and thus was used to describe age-related loss of muscle mass [8,9]. However, growing recognition that low muscle strength and/or impaired physical function are independent (and often better) predictors of mobility limitations, falls, fractures, and many other health outcomes than muscle mass alone has led to the current multi-dimensional definition of sarcopenia [[10], [11], [12], [13], [14]]. Despite this, many therapeutic pharmacological development (e.g., medications targeting myostatin/activin pathways, growth hormone/insulin-like growth factor 1 pathways, mitochondrial biogenesis, and steroid hormones) to counteract sarcopenia have mostly targeted muscle wasting, as highlighted by the comprehensive review by Rolland et al. [1]. While some of these pharmacological agents have been effective in attenuating losses in muscle mass and to a lesser extent muscle strength, these benefits have not translated into any improvements in physical function [1]. This, along with the fact that effective interventions (i.e. resistance exercise) can improve physical function with little or no muscle hypertrophy, raises the question of whether pharmacotherapies should target aspects of muscle activation/control beyond mass itself. One important area that is underappreciated in the field of sarcopenia is the impact of age-related nervous system impairments [15], especially impairments affecting spinal motoneurons, which play a key role in controlling muscle contractions (force generation) and physical function.