Repetitive TLR3 activation in the lung induces skeletal muscle adaptations and cachexia.

TitleRepetitive TLR3 activation in the lung induces skeletal muscle adaptations and cachexia.
Publication TypeJournal Article
Year of Publication2018
AuthorsGraber TG, Rawls BL, Tian B, Durham WJ, Brightwell CR, Brasier AR, Rasmussen BB, Fry CS
JournalExp Gerontol
Volume106
Pagination88-100
Date Published2018 06
ISSN1873-6815
KeywordsAnimals, Cachexia, Disease Models, Animal, Exercise Test, Immunosenescence, Male, Mice, Mice, Inbred C57BL, Muscle Contraction, Muscle, Skeletal, Muscular Atrophy, Organ Size, Poly I-C, Pulmonary Disease, Chronic Obstructive, Sarcopenia, Toll-Like Receptor 3
Abstract

Due to immunosenescence, older adults are particularly susceptible to lung-based viral infections, with increased severity of symptoms in those with underlying chronic lung disease. Repeated respiratory viral infections produce lung maladaptations, accelerating pulmonary dysfunction. Toll like 3 receptor (TLR3) is a membrane protein that senses exogenous double-stranded RNA to activate the innate immune response to a viral infection. Polyinosinic-polycytidylic acid [poly(I:C)] mimics double stranded RNA and has been shown to activate TLR3. Utilizing an established mouse viral exacerbation model produced by repetitive intranasal poly(I:C) administration, we sought to determine whether repetitive poly(I:C) treatment induced negative muscle adaptations (i.e. atrophy, weakness, and loss of function). We determined skeletal muscle morphological properties (e.g. fiber-type, fiber cross-sectional area, muscle wet mass, etc.) from a treated group ((poly(I:C), n = 9) and a sham-treated control group (PBS, n = 9); age approximately 5 months. In a subset (n = 4 for both groups), we determined in vivo physical function (using grip test for strength, rotarod for overall motor function, and treadmill for endurance) and muscle contractile properties with in vitro physiology (in the EDL, soleus and diaphragm). Our findings demonstrate that poly(I:C)-treated mice exhibit both muscle morphological and functional deficits. Changes of note when comparing poly(I:C)-treated mice to PBS-treated controls include reductions in fiber cross-sectional area (-27% gastrocnemius, -25% soleus, -16% diaphragm), contractile dysfunction (soleus peak tetanic force, -26%), muscle mass (gastrocnemius -19%, soleus -23%), physical function (grip test -34%), body mass (-20%), and altered oxidative capacity (140% increase in succinate dehydrogenase activity in the diaphragm, but 66% lower in the gastrocnemius). Our data is supportive of a new model of cachexia/sarcopenia that has potential for future research into the mechanisms underlying muscle wasting.

DOI10.1016/j.exger.2018.02.002
Alternate JournalExp. Gerontol.
PubMed ID29452288
PubMed Central IDPMC5911410
Grant ListP01 AI062885 / AI / NIAID NIH HHS / United States
T32 AG000270 / AG / NIA NIH HHS / United States
TL1 TR001440 / TR / NCATS NIH HHS / United States
T32 ES007254 / ES / NIEHS NIH HHS / United States
P30 ES006676 / ES / NIEHS NIH HHS / United States
P30 AG024832 / AG / NIA NIH HHS / United States
UL1 TR001439 / TR / NCATS NIH HHS / United States
R56 AG051267 / AG / NIA NIH HHS / United States