The Effect of Thyroid Hormones on Sarcopenia in a Chinese Elderly Population

Purpose Sarcopenia is a common disease in the elderly. The change of hormone levels with age is proposed to be involved in the pathogenesis of sarcopenia, but the effect of thyroid hormones (THs) on sarcopenia is unclear. In this study, we aimed to analyze the effect of THs on sarcopenia. Methods Total 309 elderly subjects (122 females and 187 males) with an average age of 85.19 ± 7.8 years were enrolled. Participants were divided into four groups (non-sarcopenia, sarcopenia, possible sarcopenia and serve sarcopenia) based on the consensus of the Asian Working Group for Sarcopenia in 2019. Serum levels of total triiodothyronine (TT3), free triiodothyronine (FT3), thyroxine (T4), free thyroxine (FT4), thyroid stimulating hormone (TSH), reverse triiodothyronine (rT3), and thyroxine-binding globulin (TBG) were measured. Muscle mass was measured by multifrequency bioelectrical impedance analysis (BIA). Grip was measured by spring-type dynamometer. Walking speed was represented by 6-minute walk test. Results The levels of FT3, TT3 and TSH were signicantly different in four groups. Partial correlation analysis (adjusted by age and gender) indicated that FT3, TT3 and TSH had signicant correlation with hand grip. In addition, TT3 was correlated with walking speed. Regression analysis showed that TT3 was a protective factor for sarcopenia and hand grip, and TSH was a protective factor for severe sarcopenia. Conclusions T3 plays a protective role in sarcopenia, and this effect is achieved by affecting muscle strength but not muscle mass and gait speed. Moreover, compared with FT3, this study suggested that TT3 was more suitable to evaluate the relationship between thyroid and sarcopenia in elderly.


Introduction
Sarcopenia is a common disease in elderly, which is de ned as" age-related loss of skeletal muscle (SM) mass plus loss of muscle strength and/or reduced physical performance". According to the consensus update of Asian Working Group for Sarcopenia (AWGS) in 2019, the prevalence of sarcopenia is about 7.3-12% [1][2][3]. Sarcopenia is signi cantly correlated with cardiac disease [4] and cognitive impairment [5], and increases the risk of falls and fractures [6,7]. In addition, sarcopenia increases the risk and cost of hospitalization [8], and increases mortality [9,10].
With the increase of age, muscle cross-sectional area decreases [11,12], and the types of muscle bers change [13]. SM bers are classi ed into type 1 bers and type 2 bers. Type 2 bers mainly include three types 2a, 2x and 2b [11]. Type 1 muscle bers are characterized by the expression of myosin-7 (also known as myosin heavy chain 1, MyHC ), whereas type IIa bers express myosin-2 (also known as myosin heavy chain 2a, MyHC IIa), type IIx bers express myosin-1 (also known as myosin heavy chain 2x, MyHC IIx) and type IIb bers express myosin-4 (also known as myosin heavy chain 2b, MyHC IIb). In general, the sustained contraction is mediated by type 1 bers, which are slow muscle bers, whereas type 2 bers perform short burst activities and are called fast muscle bers. The mass of muscles rich in fast muscle bers decreased, while that of muscles rich in slow muscle bers decreased little or slightly [11,14].
The pathogenesis of sarcopenia remains unclear. In addition to age [11,15], neuromuscular dysfunction[13], proin ammatory cytokines, myocyte apoptosis and heredity [16], thyroid hormones (THs) are involved in the pathogenesis of sarcopenia. THs can affect the change of muscle mass and ber types [17]. The muscle cross-sectional area is reduced in subclinical hyperthyroidism, but is improved after treatment [18], [19]. In addition, THs can promote the transition from slow muscle ber to fast muscle ber [17,20]. After the administration of triiodothyronine (T3) to the aged rats, the expression levels of MyHC IIx and MyHC IIa were upregulated in thenar muscle which was rich in slow muscle bers [21]. The relationship between THs and sarcopenia has been con rmed in animal studies. However, in clinical studies, the conclusion on the relationship between THs and sarcopenia is inconsistent [22][23][24].
The purpose of this study is to analyze the relationship between THs and sarcopenia based on clinical data, and examine the effect of THs on sarcopenia.

Subjects
Total 309 elderly subjects (aged ≥ 60 years) were included in this study, and all of them were from the Geriatric Hospital of Nanjing Medical University. Most of them were over 80 years old (n=233, 75.46%).
All the subjects had complete records of the disease history and medication history. The patients who took glucocorticoids, androgens, thyroxine and other drugs that may affect thyroid function and muscle were excluded. The subjects with thyroid dysfunction, acute infection, acute liver dysfunction, acute kidney dysfunction, stroke sequelae, Parkinson's disease and other diseases that may affect muscle function were also excluded. The study was approved by the Geriatric Hospital of Nanjing Medical University Institutional Review Board.

Assessment of grip
All subjects stood with full elbow extension, and used the hand dynamometer (CAMRY, Beijing, China) to measure the grip of the dominant hand. Three attempts with a 1-min interval and the maximum value were recorded. According to the 2019 consensus of AWGS, the low muscle strength diagnostic cutoffs of grip are <28.0 kg for men and <18.0 kg for women.
Height and weight were measured by standard methods with light clothing without shoes. Body mass index (BMI) was calculated as: BMI (kg/m 2 ) = Weight (kg)/height 2 (m 2 ). According to AWGS 2019 consensus, low SMI is <7.0 kg/m 2 in men and <5.7 kg/m 2 in women.

Assessment of gait speed
The 6-metre (6 m) walk test was used to measure gait speed (GS). According to AWGS 2019 consensus, the cutoff for slow GS is <1 m/s.

Diagnosis of sarcopenia
According to the consensus of AWGS 2019, the de nition of sarcopenia includes low SMI, combined with low grip or slow GS. Severe sarcopenia is de ned as low SMI, combined with low grip and slow GS.
Possible sarcopenia is de ned as normal SMI but low grip, with or without slow GS.

Statistical analysis
Descriptive data were presented as means (M) ± standard deviation (SD). Pearson's Partial correlation analysis was used in correlation analysis. Multiple linear regression models were applied for degrees of sarcopenia and sarcopenia elements, using age, gender and thyroid function. One-way ANOVA analysis was performed to compare baseline data, thyroid function and the sarcopenia elements among the normal, possible sarcopenia, sarcopenia and serve sarcopenia groups. All statistical analyses were performed using SPSS version 20.0 (IBM Corp, Armonk, NY, USA), and p < 0.05 was considered statistically signi cant.

Results
General characteristics, SMI, grip, GS, and THs levels of participants According to the consensus of AWGS 2019, all patients were divided into non-sarcopenia group, possible sarcopenia group, sarcopenia group and severe sarcopenia group. Among all 309 subjects, 103 were diagnosed with sarcopenia (sarcopenia and severe sarcopenia) and the prevalence rate was 33.33%, while 102 were diagnosed with possible sarcopenia and the prevalence rate was 33.01%. The baseline data of the four groups are shown in Table 1.

Discussion
Sarcopenia is one of the common diseases in the elderly. The prevalence of sarcopenia increases with age. In this study the prevalence of sarcopenia was 33.33% in the selected elderly Chinese population, similar to the results of previous study [25].
Previous studies indicated that THs participated in skeletal muscle contractile function, metabolism, myogenesis and regeneration [17,20,26]. The rats with hypothyroidism presented a delay in the switch to adult myosin in SM rich fast bers, but not in SM rich slow bers [27,28]. The muscle cross-sectional area had mild decrease in subclinical hypothyroidism rats, and THs may affect the type of muscle bers. However, some clinical studies suggested that thyroid function had no signi cant effect on sarcopenia [18]. Therefore, we performed this study to clarify the relationship between thyroid and sarcopenia.
Compared with non-sarcopenia groups, the levels of FT3, TT3, TSH in possible sarcopenia group and sarcopenia group were different, suggesting that THs might have effect on sarcopenia. In addition, partial correlation analysis showed the correlation between THs (FT3, TT3 and TSH) and elements of sarcopenia (grip and gait speed). The multiple regression analysis further con rmed that TT3 was independently associated with sarcopenia and grip, but not with SMI and GS. These results suggested that TT3 had protective effect on sarcopenia by affecting the muscle strength.
Actually, compared with TT3, FT3 plays a major physiological role in muscle [29,30], but it is also vulnerable to uctuations, especially in the elderly [29,31]. In our study, most of subjects were over 80 years old (n=233, 75.46%). We did not nd a signi cant correlation between FT3 and sarcopenia, which may be due to the uctuation of serum FT3 level in elderly patients. Although patients with acute cardiovascular and cerebrovascular diseases, acute infection and other diseases were excluded in this study, the elderly population is prone to the uctuations in FT3 level due to several factors such as age and multiple diseases. Therefore, compared with FT3, the level of TT3 may be a better indicator in the elderly population.
This study has some limitations such as small sample size, and our results need to be further evaluated by expanding the sample size. In addition, we found that TT3 was associated with sarcopenia and grip strength, but the mechanism is not clear. Further studies are needed to con rm the role of TT3 in the pathogenesis of sarcopenia.
In conclusion, this study suggested that TT3 plays a protective role in sarcopenia, and this effect is achieved by affecting muscle strength but not muscle mass and gait speed. Moreover, compared with FT3, this study suggested that TT3 was more suitable to evaluate the relationship between thyroid and sarcopenia in elderly. This study revealed that higher T3 concentration within normal range is necessary and bene cial for sarcopenia in elderly subjects.