The clinical case definition of post-COVID-19 condition (also referred to as Long COVID)
as defined by the World Health Organization (WHO) includes individuals with a history of
probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19
with symptoms and that last for at least 2 months and cannot be explained by an
alternative diagnosis. Fatigue represents one of the most frequently reported symptoms in
individuals experiencing post-COVID-19 (i.e., post-COVID-19 fatigue; PCF).Fatigue is
shown to persist for months after SARS-CoV-2 infection, negatively impacting activities
of daily living. For the purposes of this SPiRE proposal, fatigue is operationally
defined as a state characteristic encompassing a subjective lack of physical and/or
mental energy that is perceived by the individual to interfere with usual or desired
activities.

Increased fatigability is a possible complication following SARS-CoV-2 infection due to
the presence of both neuromuscular and neurobiological consequences. Skeletal muscle
alterations including reduced force capacity, fiber atrophy, mitochondria and metabolic
dysfunction, and capillary impairments have been observed in patients following
SARS-CoV-2 infection. Autopsy reports of patients who died after SARS-CoV-2 infection
found evidence of skeletal muscle atrophy of type 2 fibers, necrotizing myopathy, and
myositis. Similarly, using nerve conduction studies, patients with long-term COVID-19
were found to have signs of myopathy, even those who were not hospitalized. Evidence from
cardiopulmonary exercise testing in patients diagnosed with COVID-19 has revealed
impaired skeletal muscle oxygen extraction, as opposed to central limitations (i.e.,
cardiac output), as a determinant of exercise intolerance. In addition to neuromuscular
complications, SARS-CoV-2 infection has also been shown to be associated with psychiatric
sequelae. Collectively, these findings underscore neuromuscular as well as
neurobiological consequences of SARS-CoV-2 as potential independent or co-occurring
mechanisms by which increased fatigability occurs and persists.

Despite widespread calls for the importance of rehabilitation in individuals recovering
from SARS-CoV-2 infection, little progress has been made regarding the potential benefits
of physical exercise on fatigue and fatigability in this population. Moreover, concerns
have been raised about the applicability of physical exercise in patients recovering from
SARS-CoV-2 infection. For example, while the health and functional benefits of exercise
are vast and widely known, in certain patient populations exertion is shown to exacerbate
symptom severity. Some individuals with PCF may report experiencing worsening of symptoms
after physical or mental exertion. Home-based exercise may offer an appealing option for
those individuals concerned about attending community fitness facilities. Home-based
exercise is shown to produced moderate effects on muscle strength and balance. Presently,
the exact dosing of home-based exercise to elicit positive outcomes in fatigability is
unknown. Minimal-dose resistance exercise has been proposed as a potential strategy for
improving neuromuscular characteristics and physical function. Minimal-dose resistance
exercise uses little to no equipment with exercises performed at lower workloads. The
investigators aim to adapt the "minimal-dose" resistance exercise paradigm to a remote
home-based resistance exercise program for Veterans with PCF to determine its
implications for reducing fatigability and improving neuromuscular and neurobiological
factors. Minimal-dose resistance exercise for the proposed application is defined as a
single, weekly body-weight exercise session.