New Approaches to Understand Movement as Medicine

Abstract

This Special Section of Advanced Biology provides new insights, novel perspectives, and future directions to advance our understanding of “movement as medicine”. With a distinct translational science perspective, this section included studies ranging from molecular level transcriptome experiments in mice to late phase efficacy clinical trials of mind-body interventions. A unique combination of original investigations is presented that describes two preclinical studies of exercise training to induce neural regeneration and cardiac remodeling,^{[1, 2]} an innovative characterization of the gut microbiome within elite athletes and sedentary controls,^[3] studies on new approaches to further delineate anthropometric aspects of sarcopenia^[4] and sarcopenic obesity,^[5] a characterization of neurohemodynamic responses to acute aerobic exercise in pre-dementia older adults,^[6] the efficacy of a music-based mind-body program of Dalcroze Eurthymics for improving patient-important outcomes in older adults at high fall risk,^[7] and a comprehensive narrative review of physical, pharmacological, and multimodality therapeutic approaches to mitigate the impact of musculoskeletal diseases among individuals living with spinal cord injury (SCI).^[8]

Fang et al.^[1] sought to examine the potential molecular mechanisms of exercise-induced axonal regeneration in a mouse model of optic nerve injury. Several weeks of exercise stimulation restored DNA methylation patterns and promoted retinal ganglion cell (RGC) axon regeneration via TET3 mediated epigenetic effects. The authors then further demonstrated in a series of elegant experiments that exercise training induced RGC axon regeneration, reestablished visual circuits, partially restored vision loss, and improved metabolic function in older mice. This elucidation of the mechanistic effects of exercise-induced regeneration of these functionally important CNS neurons may allow for the further development of novel regenerative approaches to mitigate the adverse effects of optic neuropathy in humans. In another preclinical study, Han et al.^[2] examined whether a combination of endurance and resistance training could improve cardiac function. Compared to sedentary controls, aging mice underwent an 8-week intensive and progressive swimming or voluntary resistance running training regimen. This experimental approach revealed that both swimming and voluntary resistance running attenuated age-related cardiac hypertrophy and cellular senescence, cardiac metabolism, and oxidative stress, and they improved mitochondrial structure and cardiac function in these aging mice. Of other notable significance from their analyses was the identification of upstream stimulatory factor 2 upregulation in response to both training regimens, suggesting that this transcription factor warrants further investigation as a potential therapeutic target to mitigate age-related cardiac dysfunction.

In their cross-sectional study, Aya et al.^[3] provided an elegant reminder about an important yet often overlooked tenet of exercise physiology, the “specificity of training” principle. In their study, they addressed the important question as to whether divergent types of exercise training and levels of physical activity may have different influences on the gut microbiome. They compared gut microbiota among elite-level Colombian weightlifters and road cyclists compared to non-athlete controls. Their dynamic findings revealed substantially divergent microbial signatures across the three distinct study groups. Compared to non-athlete controls, weightlifters had unique microbial network connections involving viral and archaeal domains, while professional road cyclists exhibited a substantial number of connections between bacterial and archaeal families, suggesting a microbial interaction pattern modulated by the specific metabolic demands of elite level aerobic endurance type exercise.

Two clinical studies focused on anthropometric aspects of sarcopenia and sarcopenic obesity in older adults RCT. Quizzini et al.^[4] evaluated the utility of bioelectrical impedance vectors analysis (BIVA) to assess changes in cellular integrity and phase angle in response to a 12-week whole body resistance training program among older adults with sarcopenia. Comparing classic (whole-body) BIVA to a regional approach (specific limbs or trunk areas), the authors reported greater improvements in classic whole body measures indicative of possible improvements in body composition, suggestive of a decrease in fat mass and increase in fat-free mass accumulation in response to the intensive resistance training stimulus. Cook et al.^[5] examined whether absolute levels of handgrip strength or differences in handgrip strength between hands (asymmetry) were more predictive of measures of physical function in older adults with sarcopenic obesity. A major premise for this study was based on the concept that handgrip asymmetry may be indicative of early neuromuscular impairments and thus could serve as a more discriminant predictor of sarcopenic obesity in older persons. However, using baseline data from two weight loss intervention studies, the authors reported that handgrip asymmetry was highly inferior to maximal handgrip strength in predicting physical function measures in this population of older adults. While the study noted some potential utility for using concurrent assessments of maximal handgrip strength and handgrip asymmetry, it would seem that traditional measures of maximal handgrip strength should continue to be used as a diagnostic criterion for sarcopenic obesity until additional and more definitive studies can identify the prognostic utility of handgrip asymmetry in “at risk” older adults.

Two additional clinical investigations focused on examining the acute or chronic effects of exercise movement in “at-risk” older adults. Da Costa et al.^[6] characterized the mechanistic and neuro-hemodynamic responses to an acute bout of cycling exercise in older adults with motoric cognitive risk syndrome (MCR). Using functional near-infrared spectroscopy (fNIRS), the investigators characterized prefrontal cortex (PFC) oxygenation responses along with other physiological and perceptual responses to acute exercise in this high dementia risk phenotype. The authors revealed that incremental cycling exercise induced PFC oxygenation changes in an intensity-dependent manner, and these increases were positively associated with participants' self-perceived exertion levels. These encouraging findings suggested that the PFC responses to exercise in MCR were relatively consistent with prior studies in younger healthy subjects and other older adult populations. This is despite the likelihood of MCR older adults having a significant amount of underlying brain atrophy and structural and functional brain impairments. Hars et al.^[7] reported the findings from a long term (12-month) randomized comparative effectiveness trial of a Dalcroze Eurhythmics (DE) exercise program versus a traditional multicomponent exercise program among a large population of older adults at high risk for falls. The DE intervention was a music-based, education through movement approach consisting of multiple multitask exercises, sequences of movements, interaction with the movement of other participants, all performed to the rhythm of improvised piano music. DE was found to be substantially more effective than traditional exercise in reducing the incidence of falls and improving numerous other physical and cognitive outcomes among the study participants. While the integrated motor and cognitive components are likely the major ingredients that give potency to this intervention, the authors highlighted the need for future studies to delineate the specific underlying biological mechanisms through which DE can benefit older adults.

The final manuscript focused on SCI, a devastating, life-changing event that results in paralysis, reduced physical activity, and accelerated morbidity and mortality. Echevarria-Cruz et al.^[8] described the inter-linked dysregulation of cardiometabolic, musculoskeletal, and endocrine bodily organs that rapidly occurs following immobilization after SCI. This review also highlighted the profoundly deleterious issue of bone loss in SCI and how factors such as skeletal unloading, sedentary behavior, and exercise intolerance exacerbate this problem. Despite attempts at physical interventions and osteoporosis medications, there remains a dearth or effective treatments to maintain musculoskeletal health after SCI. The authors critically evaluated existing data on bone loss, fractures, and therapeutic approaches, ranging from physical to pharmacological and electrical stimulation, to mitigate SCI-associated skeletal diseases, and they highlighted important areas for future investigation.

In summary, the investigations presented in this Special Section have identified novel molecular mechanisms of exercise for counteracting neuropathy, cardiac dysfunction and how divergent modalities of exercise training can influence gut microbiota. New insights into the determinants of age-related alterations in body composition in older adults have also been provided, and the novel effects of exercise and mind-body approaches among vulnerable older adults with pre-dementia and high fall-risk, respectively, were also described. A comprehensive overview of the need to develop new therapeutic strategies, and particularly multimodality approaches, to improve outcomes among individuals with SCI, was also presented. Collectively, I believe that the aforementioned manuscripts will inspire new research endeavors that will further advance our understanding of the biological mechanisms of exercise and its multiple intrinsic and extrinsic influences on human health and functioning. I wish to thank all 59 authors who collectively contributed to this novel body of work, and the critical and constructive efforts of all peer reviewers for their exemplary contributions to this Special Section.

The authors declare no conflict of interest.