Effects of Multidomain Interventions on Sarcopenia

Sarcopenia, a complex muscular condition driven by multi-systemic dysregulation and its interactions with lifestyle, physical attributes, and mental health, lacks effective drug treatments, relying primarily on non-pharmacological interventions. Fragmented approaches may prove suboptimal due to its complexity, underscoring the potential for multidomain interventions—a combination of two or more strategies to improve individual health—as a promising treatment option. This review examines the possible roles of multidomain interventions in sarcopenia, specifically addressing their effects on muscle mass and quality, muscle strength, and physical performance in older adults. While the updated literature highlights the beneficial consequences of multidomain interventions in enhancing physical performance outcomes, gaps persist in understanding their influence on the biological aspects of sarcopenia. Promising initial findings suggest changes in plasma inflammatory markers or muscle turnover networks, but further research is necessary to clarify the disease-modifying effects of multidomain intervention in sarcopenic patients.


T
he Multidomain intervention is a broad term encompassing strategies involving at least two interventions, typically associating physical exercise, nutrition, cognitive training, or psychosocial components (1).Due to its simultaneous multiple targets, multidomain interventions are believed to promote comprehensive improvement in an individual's health and prevent disability (2).Sarcopenia is a complex geriatric syndrome characterized by the progressive loss of muscle mass or quality, reduced strength, and declining physical performance (3).It is an age-related disease with systemic impacts, contributing to disability and mortality (4), thus making it a potential candidate for multidomain interventions.Although multidomain interventions may apply as a therapeutic option for sarcopenia, the extent to which they intervene on the pathophysiology of the disease (i.e., disease-modifying effect), on sarcopenia symptoms, or on both is unknown.
The aim of this short review is to gather current data on the potential roles of non-pharmacological multidomain interventions in the treatment of sarcopenia.

Methods and Results
A comprehensive and sensitive search strategy was conducted in the PubMed database, combining multidomain and sarcopenia terms to identify relevant evidence in this field.We looked for randomized controlled trials (RCT) that operationalized a multidomain intervention in older people.Very limited research was uncovered regarding sarcopenic populations.Considering established connections between sarcopenia and frailty (5), we included studies enrolling participants with sarcopenia, pre-frailty or frailty, and mobility impairment (low short physical performance battery (SPPB) scores).
All RCTs evaluated older adults aged 65 years or older.The interventions, lasting from 12 weeks to 3 years, always comprised physical exercise, usually along with nutritional counseling or supplementation.Only two studies did not involve any nutritional strategy (6,7).Additional components like cognitive training, psychosocial support, or comorbidities management were sometimes aggregated.Further details about included studies are summarized in Table 1.
The collected data refers to the effects of multidomain interventions in each of the components of sarcopenia (muscle mass/quality, muscle strength, or physical performance).For organizational clarity, the findings are here categorized into these three components in alignment with the consensus of the European Working Group on Sarcopenia in Older People (3).Finally, information related to the biological influences of multidomain interventions (disease-modifying effects) will be presented.

Physical performance
Regarding multidomain interventions in participants diagnosed with sarcopenia, two studies identified greater improvement in the SPPB total score in the multidomain  intervention was associated with a reduced risk of mobility disability (inability to perform the 400-meter walk test) during the 36-month follow-up (8).Similar findings were seen among pre-frail/frail or mobility-impaired samples.Several studies identified greater improvement in the SPPB total score (6,7,(12)(13)(14)(15), GS (6,12,(14)(15)(16)(17) and timed-up-and-go test (TUG) (16,17) in the multidomain intervention group compared to control groups.Only three studies found no difference between groups in GS (18,19) and TUG (20).

Muscle strength
Examining samples with diagnosed sarcopenia, three studies evaluated muscle strength.Two of them found improved completion time for the 5-times chair sit-tostand test (5CST) after the intervention compared to the control group (9,10).Additionally, knee extension strength (KES) was greater in the intervention group than in the control group (10).While one study found no difference between groups in handgrip strength (HGS) after a two-year intervention (9), Bernabei et al. identified a smaller decline in HGS over the same period in women assigned to the multidomain intervention than those in the control group; however, no difference was seen among men (8).
In the two other populations, several studies also identified improvements in the 5CST (6,12,16,20,21) and lower limb strength (19,20,22) with the intervention compared to the control group, except for one study that did not find differences in KES between the groups (17).Casals et al. found a decrease in the prevalence of individuals with low HGS in the intervention group, with no significant changes observed in the control group (12).However, three other studies found no significant difference in HGS between groups (7,17,18).

Muscle mass and quality
Regarding individuals with sarcopenia, Zhu et al. identified increased appendicular skeletal muscle mass (ASM) index (ASM/height²) in the combined exerciseprogram-and-nutrition-supplement group over 12 weeks, while it decreased among controls (10).Bernabei et al. also found that women that received the multidomain intervention experienced less loss of appendicular lean mass (ALM) compared to the control group at 36 months.However, no significant differences were observed in men (8).Interestingly, in a sample of 92 sarcopenic individuals, among the three components of sarcopenia, muscle mass exhibited the least change, with only 7.6% achieving a normal ALM index (ALM/height²) after 6 months (11).In the other populations, one study observed a smaller decline in ASM index among the intervention group compared to controls.(6).Two other studies found no group differences concerning ALM (17,22), although in one of them, the control group also received physical exercise (22).
More recently, studies have analyzed muscle quality parameters using image assessment techniques such as computed tomography scans (CT) or ultrasound (US).Performing US measurements on the vastus lateralis muscle of sarcopenic individuals, Monti et al. demonstrated preserved muscle architecture (pennation angle and fascicle length) despite a reduction in crosssectional area (CSA) after the intervention.Conversely, in the control group, these architectural parameters declined along with a further decrease in CSA (9).Two studies assessed thigh measurements in mobility-impaired individuals.Within the intervention group, Englund et al. verified CT improvements in thigh composition (higher thigh muscle CSA, lower subcutaneous adipose tissue, lower intermuscular fat) (22).Skoglund et al. also observed significant increases in CT CSA and enhanced radiological attenuation, a parameter of muscle density, in knee extensors and hip adductors following the intervention.However, despite improvements in physical performance within this sample, multivariate analysis revealed that these changes were not directly associated with the alterations in muscle CSA and density postintervention (15).

Biological evaluations
Ongoing research into the pathophysiology of sarcopenia reveals a complex multisystemic dysregulation indicative of altered muscle anabolic and catabolic responses, chronic inflammation, mitochondrial dysfunction, and neuromuscular changes (23).Two of the included studies assessed biological parameters after multidomain interventions in sarcopenic individuals.Through the analysis of blood T cells, Ma et al. discovered significant differences in the expression of seven genes associated with T cell regulation and inflammation (RASGRP1, BIN1, LEF1, ANXA6, IL-7R, LRRN3, and PRKCQ) between pre-and post-intervention measurements.These differences were found to correlate with leg extension strength (24).Moreover, Monti et al. found that C-terminal agrin fragment (CAF) levels, a marker of neuro-muscular junction (NMJ) instability, remained unchanged in the intervention group.At the same time, they increased in the control group after a two-year follow-up.They also observed a correlation between better SPPB scores and lower CAF concentration.Conversely, no difference was found in plasma levels of neurofilament light chain, another marker of the motoneuron health (9).
Other authors assessed biomarkers following multidomain interventions in pre-frail/frail populations.Concerning inflammation, Caldo-Silva et al. verified that plasma tumor necrosis factor alpha (TNF-α) levels decreased in the group receiving physical exercise and branched-chain amino acids supplementation, but only after a detraining period followed by a second wave of 16 weeks of intervention (21).Tan et al. also identified a reduction of TNF-α levels after 12 weeks of intervention compared to controls (6).No differences were seen among groups for other inflammatory indicators such as interleukin (IL) 6 ( 6), IL-10 (6, 21), and myeloperoxidase (21), nor in the hematological profile (hemoglobin, erythrocyte, white blood cell, or platelet counts) (25).Markers related to nutrient sensing and muscle turnover were also assessed.One study verified lower insulin-like growth factor (IGF) Binding Protein-3 to IGF-1 plasma ratios in the multidomain group compared to placebo, alongside reduced myostatin and increased brain-derived neurotrophic factor serum levels within the group (17).After the intervention, no difference was seen concerning growth differentiation factor 15 (6), Beta-2 microglobulin (17), albumin (21), and growth hormone (17).

Final considerations and future perspectives
Sarcopenia is a multifaceted geriatric syndrome with significant implications for both individuals and society, as it is associated with quality of life, independence, morbidity, and mortality (3).As of today, there is currently no evidence supporting drug treatments for sarcopenia; strength exercise training and nutritional support remain the main management options (26).Therefore, multidomain interventions are an interesting approach, especially when combining these last two aspects.
Findings from this review, summarized in figure 1, indicate beneficial impacts of multidomain interventions on the muscular components of sarcopenia among older adults.Muscle performance appears to be the more consistently improved aspect.Greater lower limb strength measured by CST or KES was also observed.Muscle mass seems to ameliorate with multidomain intervention, probably in a smaller degree compared to the other Figure 1.A summarized framework of multidomain interventions on sarcopenia and its components, including modifications in physical manifestations and potential biological effects, according to the main findings of our review components.Conversely, the variability in improvements in HGS suggests a less uniform response.This could arise from several factors, including larger muscle mass volume, better response to interventions (27), or more pronounced age-related declines in lower limb muscle compared to the upper body (28).Moreover, lower limbs are extensively involved in weight-bearing and functional activities, and balance and mobility exercises often prioritize the lower body (29).Overall, responses seemed to be influenced by age, sex, degree of baseline impairment, and the type of intervention.Although not within this review's scope, it's important to recognize that since all studies combined physical exercise with another modality, and typically compared the intervention to a control group, the exclusive effect of physical exercise cannot be ruled out.
While multidomain interventions demonstrate a more consistent impact on the physical manifestations of sarcopenia, there is still limited understanding of their pathophysiology effects.Recent research delves into qualitative changes in the muscle, with modifications in architectural parameters and intramuscular fat being seen even without major changes in muscle mass.Furthermore, there may be primary effects concerning some inflammatory markers, nutrient sensing, and muscle turnover networks, or measurements of the neuromuscular junction.Still, current data is derived from a limited number of studies with small sample sizes, often lacking comprehensive analysis of biological parameters and their correlation with physical outcomes.Future research addressing larger populations aimed specifically at sarcopenic patients is needed, with a special focus on the biological primary pathways and disease-modifying effects of multidomain interventions.

Table 1 (
Continued).Summarized information on studies included in the review (11))vention group compared to control group(8,9).While one study found no differences between groups in gait speed (GS) after 12 weeks of intervention (10), Lu et al. identified that among the components of sarcopenia, GS exhibited the greatest change associated with multidomain intervention, with 22 out of 30 participants becoming free of low GS after 6 months(11).Moreover, in a multicenter European study involving 1519 older adults, a subgroup analysis of participants with lower SPPB score (3 to 7) revealed that the multidomain

Table 1 (
Continued).Summarized information on studies included in the review