Cardiac troponin I and T transcripts are detectable in skeletal muscle of patients hospitalized with non-cardiac disease

Background Cardiac troponins (cTn) are central to the diagnosis of acute coronary syndrome. Fulfilment of the criteria for myocardial injury (cTn>99th percentile) is common in non-cardiac diseases and cTn-release mechanisms remain incompletely understood. Cardiac troponin T (cTnT) release from skeletal muscle has been demonstrated in patients with skeletal muscle disorders. We hypothesized that re-expression of fetal cTn transcripts occurs in skeletal muscle of hospitalized patients without primary skeletal myopathy. Purpose To investigate skeletal muscle mRNA expression of cardiac and skeletal troponin isoforms in hospitalized patients with rhabdomyolysis (rhabdo), sepsis, and chronic kidney disease stage 5 (CKD5) compared with healthy controls. Methods In this prospective single-center study, patients with rhabdo (n=28), sepsis (n=49), and CKD5 (n=48) were enrolled within 48 hours of admission. All underwent ECG, echocardiography and high-sensitivity cTn measurement; patients with underlying cardiac disease were excluded. Patients with cTnT >99th percentile, underwent fine-needle biopsy of the vastus lateralis muscle. Relative gene expression was quantified by RT-qPCR (TaqMan assays). Cardiac (TNNT2, TNNI3) and skeletal muscle troponin genes (TNNT1, TNNT3, TNNI1, TNNI2) were analyzed. Expression levels were normalized to PPIA (housekeeping gene) and calculated using the 2−ΔΔCt method relative to controls. Between-group differences were assessed using Welch’s t-test on ΔCt values without multiple-testing correction. Results Biopsies were obtained from controls (n=10), patients with sepsis (n=5), rhabdomyolysis (n=6), and CKD5 (n=7). All skeletal troponin gene-transcripts were downregulated in sepsis compared with controls (all p≤0.038) (figure 1). A similar downregulation was observed in patients with rhabdo for TNNI1, TNNI2 and TNNT3 (all p≤0.036). For the cTn genes, TNNI3 was significantly downregulated in sepsis (ΔCt difference 2.51 [95% CI −4.33 to −0.69], p=0.016), with a similar but non-significant trend in rhabdo (p=0.061). No significant changes were observed for TNNI3 in CKD5. In contrast, TNNT2 was not reduced in sepsis or in rhabdo and differed significantly in CKD5 (ΔCt difference −1.64 [95% CI 0.30 to 2.98], p=0.020), indicating relatively preserved or higher TNNT2 expression compared with controls. Conclusion Cardiac troponin transcripts were detectable in skeletal muscles in both healthy individuals and hospitalized patients with CKD5, Rhabdo and sepsis. Overall, acute systemic illness was associated with broad downregulation of skeletal muscle troponin gene transcripts, whereas TNNT2 expression appeared preserved and relatively increased in CKD5. These findings suggest disease-specific regulation of cTn genes in skeletal muscle and potential contribution to circulating cTn patterns. Confirmation at the protein level is warranted to clarify the contribution of skeletal muscle to circulating cTn.