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Hypoxia, a systemic condition defined by inadequate oxygen delivery to tissues, may arise from reduced environmental oxygen availability, as it occurs at high altitudes and in critically buried avalanche victims, or from any restriction to the oxygen flux along the oxygen cascade from atmosphere to mitochondria (Samaja & Ottolenghi, 2023). In pulmonary diseases the major barrier to the oxygen flux lies either at the air–alveolar interface or across the alveolar–capillary membrane, resulting in arterial hypoxemia. Such a condition often coexists with hypercapnia, similar to what happens in victims breathing into avalanche debris (Strapazzon et al., 2024). By contrast altitude hypoxia is typically associated with increased ventilatory drive and hypocapnia. These divergent patterns underscore a fundamental yet underappreciated paradigm whereby oxygen and CO2 are regulated through distinct physiological logics. Therefore hypoxemia and hypercapnia frequently overlap in determining morbidity and mortality chronically in pulmonary patients and acutely in avalanche victims. Disentangling the underlying biological effects remains challenging, with the dysfunction induced by these conditions spanning multiple organ systems − cardiovascular, renal, cerebral and pulmonary − with skeletal muscle emerging as a major determinant of functional decline and adverse clinical outcomes. Despite substantial experimental and clinical work, attempts to discriminate the specific contributions of hypoxemia and hypercapnia to muscle dysfunction have yielded inconsistent results. In this context the article published in this issue of The Journal of Physiology by Balnis and Jaitovich represents a timely and rigorous effort to clarify how hypoxemia and hypercapnia independently and jointly drive skeletal muscle dysfunction (Balnis & Jaitovich, 2026). A major strength of this article lies in its attempt to disentangle mechanisms that are frequently conflated in both experimental design and clinical interpretation. Although no single study can fully capture the complexity of muscle dysfunction in acute and chronic respiratory diseases and other conditions related to environmental exposure, Balnis and Jaitovich went beyond reductionist paradigms towards a more integrated, system-level framework encompassing the organism responses to abnormal oxygen and CO2 tensions. As a matter of fact, one of the most striking aspects emerging from this synthesis is how two small gaseous molecules can elicit so profoundly different signalling cascades while converging on a common phenotype: loss of skeletal muscle mass and function. Hypoxemia primarily activates pathways downstream of hypoxia-inducible factors (HIFs), with coordinated regulation of protein synthesis and degradation, autophagy, mitochondrial oxidative capacity and myosin heavy chain isoform expression. These changes, in turn, influence muscle regenerative capacity and epigenetic programmes governing long-term tissue integrity. By contrast hypercapnia exerts many of its effects through intracellular acidosis, triggering signalling pathways that may overlap with those activated by hypoxia. Notably elevated CO2 and reduced pH can antagonize both HIF- and AMPK-dependent signalling, adding a further layer of complexity to cellular energy sensing. From an evolutionary perspective this divergence is particularly compelling: atmospheric CO2 preceded oxygen by billions of years, suggesting that adaptive responses to abnormal levels of these gases are distinct and evolutionarily conserved. The article by Balnis and Jaitovich provides especially valuable insight into redox biology. Hypoxia is classically associated with mitochondrial dysfunction and increased production of reactive oxygen and nitrogen species, whereas CO2 can modulate redox signalling through hypoxia-independent mechanisms. This distinction reinforces the concept that hypercapnia is not merely a modifier of hypoxic stress but an independent biological driver of muscle dysfunction. Organizing skeletal muscle pathology into three functional domains − muscle mass, metabolic/oxidative properties and regenerative capacity − the authors show that hypoxemia and hypercapnia converge on atrophy through distinct upstream regulators, which include Akt, mTORC1, AMPK and HIF-1. In their article, Balnis and Jaitovich also expose critical gaps that warrant future investigation. These include the role of acidaemia-induced Na+/H+ exchange and its impact on intracellular Ca2+ handling and ATP consumption; the frequent coexistence of anaemia in pulmonary disease and polycythaemia in high-altitude adaptation; the contribution of systemic inflammation; and the differential handling of nitric oxide, which may profoundly shape vascular and muscular responses to hypoxemia versus hypercapnia. Addressing these issues will require experimental models that better reflect the complexity of human disease, but the most provocative implication of this article is perhaps the need to reassess CO2 from a passive by-product of metabolism to a pervasive chemical regulator of several body functions. In fact CO2 is the primary driver of ventilation via central and peripheral chemoreceptors, a key determinant of acid–base homeostasis, a critical modulator of oxygen release from haemoglobin and a tonic vasodilator, particularly in the cerebral and peripheral circulation. Importantly being CO2 produced by every nucleated cell as a product of the tricarboxylic acid cycle, it is also a ‘universal’ regulator rather than a specialized hormonal signal. Emerging evidence indicates that CO2 can modulate gene expression, inflammation and immune responses, further expanding its physiological relevance. Although its role in coronary circulation is secondary to local metabolic control, CO2 participates in coupling tissue metabolism to blood flow in multiple vascular beds and can have a detrimental role to determine cerebral hypoxia due to its effect on systemic blood, as well as cerebral perfusion pressure. CO2 also seems to elicit detrimental acute effect reducing muscle contractility in acute hypercapnia. By reframing hypoxemia and hypercapnia as biologically distinct yet intersecting stressors, the article by Balnis and Jaitovich advances our understanding of skeletal muscle dysfunction in respiratory disease and other conditions related to environmental exposure. More specifically this article emphasizes the raising need to integrate CO2 biology into models of hypoxic disease. In doing so, it provides a valuable conceptual roadmap for both basic scientists and clinicians − and invites a broader reconsideration of CO2 not merely as metabolic waste, but as a fundamental regulator of physiology both when decreased or increased. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. None declared. All authors have approved the final version of the manuscript and agree to be accountable for all aspects of the work. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. None.