Last Word on Viewpoint: The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathies.

We greatly appreciate the interest and Commentaries (6) provided by several authors regarding our recent Viewpoint on COVID-19 and skeletal muscle susceptibility (2). Given the salient perspectives provided by all, we hope to offer a final word.

In our Viewpoint, we had attempted to highlight a potential mechanism of SARS-CoV-2 infection on skeletal muscle cell types via the ACE2 receptor. However, several authors have pointed out that the systemic proinflammatory milieu induced by COVID-19 may indirectly contribute to skeletal muscle consequences. While we agree the COVID-19-induced cytokine storm indeed plays an important role in the pathophysiology of various organ systems, including skeletal muscle (5), the intrinsic expression of ACE2 receptor, a key entry point of SARS-CoV-2, in skeletal muscle likely contributes to the direct entry of SARS-CoV-2 into the skeletal muscle and associated skeletal muscle morbidities.

As several authors remarked, appropriately periodized routine exercise training may potentially improve COVID-19 outcomes. Specifically, aerobic exercise acutely augments the ACE2 activity (3), which has anti-inflammatory and anti-fibrotic effects in skeletal muscle (1). Since ACE2 is the primary route of cellular entry for SARS-CoV-2, which downregulates ACE2 expression (4), the challenge is to understand if upregulation of ACE2 in response to exercise is favorable or unfavorable to COVID-19-related muscle morbidities. The upregulation of ACE2 may have a favorable effect on vasodilation and negative effects on inflammation and fibrosis. However, the increased ACE2 expression in skeletal muscle after exercise will likely have a direct entry point for SARS-CoV-2. Given the myriad of health benefits gained from regular physical activity, we support chronic exercise as an invaluable therapeutic tool for many human diseases and disorders. In agreement with this, the exercise-induced skeletal muscle adaptation may revoke the consequence of ACE2-SARS-CoV-2. However, further studies are required for a definitive conclusion for whether ACE2 augmentation in skeletal muscle is beneficial or deleterious to SARS-CoV-2.

Sentiments gleaned from the supplied Commentaries suggest that new COVID-19 risk-stratification scores should incorporate respiratory muscle weakness (RMW). Accordingly, we concur that RMW should be viewed as an important factor in the context of COVID-19 risk and overall prognosis. We also share similar concerns posed by several authors regarding potential long-term muscle perturbations following SARS-CoV-2 infection. Taken together, skeletal muscle exists as a uniquely important organ system in the progression of and recovery from COVID-19.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

P.J.F., S.E.A., and J.S.M. drafted, edited, revised, and approved final version of manuscript.