Introduction
Sarcopenia is a generalized skeletal muscle disorder that involves the progressive loss of muscle mass and function [
1], leading to substantial functional decline, development of chronic diseases, disability, and frailty [
2‐
5]. The European Working Group on Sarcopenia in Older People (EWGSOP) developed a set of clinical guidelines and consensus diagnostic criteria, which emphasized on the presence of low muscle strength and low muscle mass as the definition of sarcopenia with physical performance being only a severity gradient [
6]. Sarcopenia that is largely related to age in the absence of other identifiable cause is defined as primary sarcopenia. Sarcopenia is considered ‘secondary’ when factors other than age are identified [
6]. The mechanisms associated with the development and progression of sarcopenia include endocrine dysfunction [
7], neuro-degenerative diseases [
8], malnutrition [
9], cachexia [
10], aging [
10], disuse [
11], and cellular dysfunctions [
12]. Studies had pointed out the significances of mitochondrial dysfunction in the pathogenesis of sarcopenia [
12‐
15]. However, the associated pathway of mitochondrial dysfunction leading up to sarcopenia is still unclear. More researches and clinical studies on mitochondrial dysfunction induced sarcopenia are required.
Several researchers have outlined that decreased hemoglobin is linked to sarcopenia [
16‐
18]. While anemia is evidently associated with sarcopenia, investigation regarding non-anemic individuals with sarcopenia development is warranted. We suspect that the heme biosynthetic pathway, which takes place in mitochondria, responsible for the generation of hemoprotein constituent is related to the development of sarcopenia. Protoporphyrin IX (PPIX) is the final intermediate in the heme biosynthetic pathway. PPIX is a heterocyclic organic compound that exhibits biological functions by chelating to transition metals to form metalloporphyrins [
19]. A mice study highlighted accumulating PPIX mediated alterations in mitochondrial membrane potentials and formation of fragmented mitochondria in hepatocytes [
20]. PPIX is commonly converted to heme by chelating to iron under the catalyzation of an enzyme known as ferrochelatase [
19]. Nevertheless, the heme biosynthetic pathway could get interrupted under low iron concentration and lead toxicity. This results in the substitution of other transitional metals, particularly zinc, for iron during the chelation, causing an increase in zinc PPIX level [
21]. Taken together, PPIX plays a critical role as an intermediate of heme biosynthetic pathway in which a sustained homeostasis is required.
In this study, we hypothesize that alterations in serum PPIX concentration may play a role in the pathogenesis of sarcopenia. As no previous studies had investigated the association between PPIX and sarcopenia, we conducted a cross-sectional study on a group of nationally representative United States adult population to examine this issue.
Discussion
The present study closely inspected the relationship between the PPIX concentration in a nationally representative sample of the United States adult population and the components of sarcopenia. Our results indicated strong relationships between PPIX concentrations and sarcopenia. The same correlations in participants with low serum iron concentrations were also observed. To the best of our knowledge, the present study was the first to investigate the role of PPIX in predicting sarcopenia in a group of 1172 males and females.
The development of sarcopenia is multicausal and remains controversial owing to its complex nature in pathogenesis. Current studies had discovered multiple factors that represent strong associations with the development of sarcopenia [
35‐
37]. The reduction in mitochondrial biogenesis and its respective cellular changes were recognized as major contributing factors in the progression of sarcopenia [
14,
38]. A decline in the functions of mitochondria was found to be associated with pathologic events such as Type 2 diabetes and Alzheimer’s disease, both of which were common in the geriatric population [
39].
Mitochondrial biogenesis is responsible for the clearance of damaged mitochondria and prompts the generation of new mitochondria [
40]. The process of mitochondrial biogenesis is prone to the destructive effects of toxins and environmental exposures [
41]. Heme oxygenase-1 (HO-1), on the other hand, plays a protective role in the elimination of dysfunctional mitochondria and the stimulation of mitochondrial biogenesis [
42,
43]. Recent studies by Takanche stressed the upregulating effects HO-1 had on antioxidant gene and mitochondrial biogenesis [
40,
44]. An animal study on rat by Chen et al. explained the role of HO-1 in the expression of miR-27b, which increased mitochondrial biogenesis and suppressed systemic inflammation [
45]. We speculate that HO-1 inhibitor zinc PPIX, which forms under the lack of iron reservoir, may implicate the cause behind the positive correlation between PPIX and components of sarcopenia. While increased expression of miR-27b mediated cytoprotective modulation in mitochondria, the coadministration of zinc PPIX reversed the regenerating activities of HO-1 [
46]. Yu et al. also observed the similar inhibitory effects of zinc PPIX on the attenuation of mitochondrial biogenesis and anti-inflammation induced by HO-1 and Tetrahydroxystilbene glucoside [
47]. Taken together, zinc PPIX entails sarcopenia via inducing inhibition on mitochondrial biogenesis. These discoveries were consistent with our finding, which illustrated positive association between PPIX concentration and components of sarcopenia. Our results also indicated the equivalent association under low serum iron concentration, supporting the formation of zinc PPIX and its subsequent inhibitory activities.
In addition to the augmentation in mitochondrial biogenesis, HO-1 had also been found to exhibit anti-inflammatory and neuroprotective properties in rats [
48,
49]. Yu et al. discovered in their experiments that HO-1 inhibited muscle fiber atrophy through suppressing proinflammatory cytokines and downregulating specific enzyme activation [
48]. Although they did not observe effects of zinc PPIX on HO-1 expression, they did recognize suppressed HO-1 activation caused by zinc PPIX. Khan et al., in their animal models, demonstrated the therapeutic effects of increased HO-1 in neurodegenerative disorders such as Alzheimer disease and Parkinson disease [
49]. Their study also identified tin PPIX, also a HO-1 inhibitor, as the reversal agent of the cytoprotective effects of HO-1. According to accumulating studies, the buildup of PPIX caused degenerative mitochondrial function, inflammation, and reduced cytoprotection. The accumulation of PPIX and its inhibitory nature implicates intrinsic role in the development of sarcopenia.
The present study has several strengths. While the screening involved in sarcopenia has been clearly identified in the EWGSOP guideline, a predictive biomarker for sarcopenia is lacking. Through our research, we offered PPIX as a highly potential biomarker in the prognostic prediction of sarcopenia. Moreover, the study included a large sample of older adults with racially mixed sample in the demographics to examine the associations. A defined biomarker such as PPIX proposed in the current study may assist clinical settings in diagnosing sarcopenia through blood analysis. This is not only effective, but also economical in comparison to physical performance tests. Further researches should aim towards establishing analytical validation of the proposed biomarker as well as qualification of the biomarker.
Several limitations in the present study should be noted. First, the study is a cross-sectional study. Thus, a causal relationship between PPIX and sarcopenia cannot be established. Long term observations are required to validate the relationship. Second, information such as participants’ medical histories and education levels were based on self-reported response to questionnaires. The effects of recall bias and other unknown errors may cause distortion in results. Third, the design of the current study may have been subjected to selection bias. This may lead to inaccurate representation of the relationship. Lastly, participants’ cognitive status [
50], drug consumption [
51], and nutritional status [
52] were crucial factors of sarcopenia that were not taken into account. Thus, the effects of confusion bias could not be overlooked.
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