Cardiomyocytes, similarly to cells in various tissues, are responsive to mechanical stress of all types, which is reflected in the significant alterations to their electrophysiological characteristics. This phenomenon, known as mechanoelectric feedback, is based on the work of mechanically gated channels (MGCs) and mechano-sensitive channels (MSCs). Since microgravity (MG) in space, as well as simulated microgravity (SMG), changes the morphological and physiological properties of the heart, it was assumed that this result would be associated with a change in the expression of genes encoding MGCs and MSCs, leading to a change in the synthesis of channel proteins and, ultimately, a change in channel currents during cell stretching. In isolated ventricular cardiomyocytes of rats exposed to SMG for 14 days, the amount of MGCs and MSCs gene transcripts was studied using the RNA sequencing method by normalizing the amount of “raw” reads using the Transcripts Per Kilobase Million (TPM) method. Changes in the level of channel protein, using the example of the MGCs TRPM7, were assessed by the Western blot method, and changes in membrane ion currents in the control and during cardiomyocyte stretching were assessed by the patch-clamp method in the whole-cell configuration. The data obtained demonstrate that SMG results in a multidirectional change in the expression of genes encoding various MGCs and MSCs. At the same time, a decrease in the TPM of the MGCs TRPM7 gene leads to a decrease in the amount of TRPM7 protein. The resulting redistribution in the synthesis of most channel proteins leads to a marked decrease in the sensitivity of the current through MGCs to cell stretching and, ultimately, to a change in the functioning of the heart.

L-type Ca²⁺ channels, particularly Ca_V1.2, play a crucial role in cardiac excitation-contraction coupling and are known to exhibit mechanosensitivity. However, the mechanisms regulating their response to mechanical stress remain poorly understood. To investigate the mechanosensitivity and nitric oxide (NO)-dependent regulation of L-type Ca²⁺ channels in rat ventricular cardiomyocytes, we used RNA sequencing to assess isoform expression and whole-cell patch-clamp recordings to measure L-type Ca²⁺ current (I_Ca,L) under controlled mechanical and pharmacological conditions. RNA sequencing revealed predominant expression of Ca_V1.2 (TPM: 0.1170 ± 0.0075) compared to Ca_V1.3 (0.0021 ± 0.0002) and Ca_V1.1 (0.0002 ± 0.0002). Local axial stretch (6–10 μm) consistently reduced I_Ca,L in proportion to stretch magnitude. The NO donor SNAP (200 μM) had variable effects on basal I_Ca,L in unstretched cells (stimulatory, inhibitory, or biphasic) but consistently restored stretch-reduced I_Ca,L to control levels. Ascorbic acid (10 μM), which reduces S-nitrosylation, increased basal I_Ca,L and partially restored the reduction caused by stretch, implicating S-nitrosylation in channel regulation. The sGC inhibitor ODQ (5 μM) decreased I_Ca,L in both stretched and unstretched cells, indicating involvement of the NO–cGMP pathway. Mechanical stress modulates L-type Ca²⁺ channels through a complex interplay between S-nitrosylation and NO–cGMP signaling, with S-nitrosylation playing a predominant role in stretch-induced effects. This mechanism may represent a key component of cardiac mechanotransduction and could be relevant for therapeutic targeting in cardiac pathologies involving mechanically induced dysfunction.

Although hypergravity may influence cardiac mechanosensitivity, the effects on specific ion channels remain inadequately understood. This research examined the effects of long-term hypergravity on the functional activity and transcriptional expression of mechanosensitive channels (MSCs) in rat ventricular cardiomyocytes. After 14 days of exposure to 4g, rats were subjected to molecular and electrophysiological analyses. Significant remodeling of MSC-encoding genes was revealed by RNA-seq. Trpm7 (+41.23%, p = 0.0073) and Trpc1 (+68.23%, p = 0.0026) were significantly upregulated among non-selective cation channels, while Trpv2 (−62.19%, p = 0.0044) and Piezo2 (−57.58%, p = 0.0079) were significantly downregulated. Kcnmb1 (−47.84%, p = 0.0203) was suppressed, whereas Traak/K2P4.1 showed a strong increase (+239.48%, p = 0.0092), among K⁺-selective MSCs. Furthermore, Kir6.1 was significantly downregulated (−75.8%, p = 0.0085), whereas Kir6.2 was significantly upregulated (+38.58%, p = 0.0317). These results suggest targeted transcriptional reprogramming that suppresses pathways associated with maladaptive Ca²⁺ influx while enhancing Ca²⁺-permeable mechanosensitive channels alongside stabilized K⁺ conductance. At the structural level, cardiomyocytes from hypergravity exposure showed a 44% increase in membrane capacitance, consistent with hypertrophic remodeling, and sarcomere elongation (p < 0.001). Functionally, stretch-activated current (I_SAC) was markedly hypersensitive in patch-clamp analysis: currents were induced at very small displacements (1–2 µm) and were significantly larger under 4–10 µm stretch (222–107% of control values). These findings indicate that chronic hypergravity induces coordinated molecular, structural, and functional remodeling of cardiomyocytes, characterized by increased membrane excitability, compensatory stabilizing mechanisms, and enhanced Ca²⁺ signaling. This demonstrates the flexibility of cardiac mechanotransduction under prolonged gravitational stress, with potential implications for understanding cardiovascular risks, arrhythmias, and hypertrophy associated with altered gravity environments.