Muscle function outweighs appendicular lean mass in predicting adverse outcomes: Evidence from Asian longitudinal studies

Dear Editor,

Sarcopenia, originating from the Greek expression “poverty of flesh” [1], was introduced by Dr. Rosenberg in 1989, focusing appendicular muscle mass loss. Over the past decades, this concept has gained prominence in scientific literature, now defined as a progressive skeletal muscle disorder characterized by an accelerated decline in both muscle mass and related function [2]. The European Working Group on Sarcopenia in Older People (EWGSOP) initially defined sarcopenia as low appendicular lean mass (ALM) coupled with either low muscle strength or reduced physical performance [3]. The International Working Group on Sarcopenia (IWGS) proposed comparable criteria [4]. In 2018, EWGSOP updated the definition, emphasizing low muscle strength as the primary characteristic [5]. The Asian Working Group for Sarcopenia (AWGS) adapted these criteria for Asian populations, accounting for distinctive features related to body composition, dietary habits, and diverse ethnic, socio-cultural, and lifestyle factors [[6], [7], [8]].

While earlier research showed low muscle mass alone predicts adverse outcomes [9], recent evidence suggests muscle function has superior prognostic significance [[10], [11], [12]]. We investigated the association between ALM and all-cause mortality, adjusting for muscle strength, using data from Japanese and Taiwanese longitudinal cohort studies: namely the National Institute for Longevity Sciences-Longitudinal Study of Aging (NILS-LSA), I-Lan Longitudinal Aging Study (ILAS), and Longitudinal Aging Study of Taipei (LAST).

ALM was estimated using dual-energy X-ray absorptiometry (DXA; QDR-4500, Hologic, Bedford, MA, USA) in NILS-LSA, Lunar Prodigy instrument (GE Healthcare, Madison, WI, USA) in ILAS, and bioelectrical impedance analysis (InBody S10, InBody Japan Inc., Tokyo, Japan) in LAST. Low ALM was defined per AWGS criteria: the lowest sex-specific quintile among middle-aged participants (aged 40–64 years), and relative appendicular skeletal muscle (RASM; calculated as ALM (kg)/height² (m²)) <7 kg/m² for men and <5.4 kg/m² for women aged ≥65 years in NILS-LSA and ILAS. In LAST, the cut-offs were the lowest sex-specific quintile in middle age and RASM <7 kg/m² for men and <5.7 kg/m² for women aged ≥65 years using bioelectrical impedance analysis (BIA). Muscle strength was evaluated using calibrated handgrip dynamometers (Takei Co., Niigata, Japan for NILS-LSA; TTM, Tokyo, Japan for ILAS and LAST), with low muscle strength defined as <28 kg for men and <18 kg for women.

Baseline surveys were conducted from Jul. 2010 to Jul. 2012 for NILS-LSA, Aug. 2011 to May 2014 for ILAS, and May 2016 to Jan. 2022 for LAST. Participants were followed up until death or loss to follow-up. Mortality data were obtained from the Vital Statistics database for NILS-LSA participants (up to Dec 31, 2017; median follow-up 6.4 years), through tri-monthly telephone interviews in LAST (up to Aug 31, 2023; median 5.6 years) and ILAS (up to Jun 30, 2022; median 9.5 years). Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality risk associated with low versus normal ALM, adjusted for baseline age, sex, and grip strength. All statistical analyses were performed using R software (version v4.3.2; R Foundation for Statistical Computing, Vienna, Austria). Two-sided exact P-values below 0.05 were considered statistically significant.

The number of participants, mortality events, and mortality/1000 person-years are shown in Table 1. Results (Fig. 1) showed low ALM was associated with mortality, especially in older participants. Lower muscle strength was associated with mortality and participants with low muscle strength had an increased mortality risk in NILS-LSA, ILAS, and the pooled data. These findings support prioritizing muscle strength over ALM when evaluating sarcopenia and related health risks in Asian populations. The discrepancy between ALM and strength in predicting mortality may be due to distinct pathophysiological mechanisms. Muscle strength, influenced by ALM, muscle composition [13], and neuromuscular function, may better indicate overall muscle health and physical capacity.

Table 1.

Basic information on number of participants, mortality events, and mortality/1000 person-years.

		NILS-LSA			ILAS			LAST			Pooled data
		No. of participants	No. of mortality	Mortality/1,000 person-years	No. of participants	No. of mortality	Mortality/1,000 person-years	No. of participants	No. of mortality	Mortality/1,000 person-years	No. of participants	No. of mortality	Mortality/1,000 person-years
All participants (≥40 years)
No. of participants		2,277			1,794			1,464			5,535
Low muscle mass	No	1,781	50	4.43	1,496	134	9.59	1,100	41	6.85	4,375	179	6.39
	Yes	496	43	14.04	298	39	14.55	364	13	6.73	1,160	82	11.63
Middle-aged participants (40−<65 years)
No. of participants		1,351			1,061			378			2,790
Low muscle mass	No	1,130	10	1.40	883	35	4.18	321	3	1.50	2,332	36	2.31
	Yes	221	2	1.42	178	12	7.32	57	2	5.88	458	11	3.69
Older participants (≥65 years)
No. of participants		926			733			1,086			2,745
Low muscle mass	No	651	40	9.73	613	99	17.69	779	38	9.53	2,043	143	11.51
	Yes	275	41	24.86	120	27	25.92	307	11	6.92	702	71	17.44
Men
No. of participants		1,158			843			483			2,484
Low muscle mass	No	882	26	4.68	705	83	12.61	397	24	11.45	1,975	100	7.90
	Yes	276	38	22.73	138	33	27.82	86	9	20.57	509	70	22.65
Women
No. of participants		1,119			951			981			3,051
Low muscle mass	No	899	24	4.19	791	51	6.90	703	17	4.37	2,400	79	5.14
	Yes	220	5	3.60	160	6	4.02	278	4	2.68	651	12	3.03

Fig. 1.

Associations between muscle mass and muscle strength and mortality (analyzed by Cox proportional hazard model and baseline age (in years; continuous) and sex were adjusted in all models).

Recent evidence pointed out a low prevalence [14] and poor agreement among sarcopenia definitions in community-dwelling cohorts [15], highlight challenges in developing sarcopenia diagnosis criteria [7]. Emerging technologies like MRI or D3 creatinine dilution method (which provide more accurate muscle mass measurements) would significantly impact future sarcopenia diagnosis, potentially leading to refined diagnostic criteria (with more precise cutoff points), earlier detection (of muscle mass loss), and new insights into muscle composition and function. Our study focused on mortality as the primary outcome. Future research should investigate associations between ALM, muscle strength, and other clinically relevant outcomes like physical disability, falls, and quality of life, to further elucidate the implications of these sarcopenia components in Asian populations.

Ethics approval and consent to participate

The Committee on the Ethics of Human Research of the National Center for Geriatrics and Gerontology (No. 1665-2), Institutional Review Board of National Yang Ming University (YM103008) and Taipei Veterans General Hospital (2018-05-003B), and Institutional Review Board of National Yang Ming University (104121F-8) approved the study protocol for NILS-LSA, ILAS, and LAST, respectively. The study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Written, informed consent was obtained from all participants prior to their inclusion in the study. The authors certify that they do and will comply with the ethical guidelines for authorship and publishing in the Journal of Cachexia, Sarcopenia and Muscle.

Funding

The NILS-LSA was supported by grants from Research Funding for Longevity Sciences from the National Center for Geriatrics and Gerontology, Japan (grant number 24-10). The ILAS was supported in part by grants from the National Science and Technology Council (NSTC <GN2>1</GN2>12-2923-B-A49-002-MY2 and NSTC 112-2622-8-A49-016-IE), the Taipei Veterans General Hospital (113VACS-001), and the Interdisciplinary Research Center for Healthy Longevity of National Yang Ming Chiao Tung University from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education in Taiwan (113W033101). The LAST was supported by grants from the Interdisciplinary Research Center for Healthy Longevity of National Yang Ming Chiao Tung University from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan (113W033101). These funders had no role in the design, conduct, or reporting of this study.

Declaration of competing interest

The authors have no actual or potential conflicts of interest to report.