Neuromuscular junction instability and altered intracellular calcium handling as early determinants of force loss during unloading in humans

Monti, Elena; Reggiani, Carlo; Franchi, Martino V.; Toniolo, Luana; Sandri, Marco; Armani, Andrea M.; Zampieri, Sandra; Giacomello, Emiliana; Sarto, Fabio; Sirago, Giuseppe; Murgia, Marta; Nogara, Leonardo; Marcucci, Lorenzo; Ciciliot, Stefano; Šimunič, Boštjan; Pišot, Rado; Narici, Marco V.

doi:10.1113/jp281365

Cited by 63 publications

(143 citation statements)

References 113 publications

(292 reference statements)

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“…Previous work with ground-based and spaceflight models in both rodents and humans have demonstrated that the postural soleus undergoes a fiber type shift towards a faster phenotype and that the muscle displays significant atrophy and weakness [ 3 , 5 , 7 , 10 , 12 , 17 , 31 , 32 , 33 , 34 , 35 ]. Furthermore, previous work has suggested a potential role for Ca 2+ dysregulation [ 11 , 12 ] in the ensuing muscle atrophy and remodeling. Others have also shown changes in SERCA isoform mRNA levels with spaceflight and Earth-based unloading—suggesting that spaceflight can alter SERCA transcription [ 9 , 16 , 17 ].…”

Section: Discussionmentioning

confidence: 99%

“…Not surprisingly, the reduction in muscle mass has also been associated with muscle weakness [ 10 ]. However, a recent study highlights the fact that skeletal muscle unloading causes disproportionate losses in muscle mass and strength, with the decline in muscle strength occurring at a faster rate than muscle mass [ 11 ]. While this suggests that the muscle weakness caused by unloading is not merely due to a reduction in muscle size, the underlying cellular mechanisms behind this disproportionate loss in muscle force are still poorly understood, and some have suggested a role for Ca 2+ dysregulation and increased reactive oxygen/nitrogen species (RONS) production [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

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Characterizing SERCA Function in Murine Skeletal Muscles after 35–37 Days of Spaceflight

Braun

Geromella

Hamstra

et al. 2021

IJMS

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It is well established that microgravity exposure causes significant muscle weakness and atrophy via muscle unloading. On Earth, muscle unloading leads to a disproportionate loss in muscle force and size with the loss in muscle force occurring at a faster rate. Although the exact mechanisms are unknown, a role for Ca2+ dysregulation has been suggested. The sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) pump actively brings cytosolic Ca2+ into the SR, eliciting muscle relaxation and maintaining low intracellular Ca2+ ([Ca2+]i). SERCA dysfunction contributes to elevations in [Ca2+]i, leading to cellular damage, and may contribute to the muscle weakness and atrophy observed with spaceflight. Here, we investigated SERCA function, SERCA regulatory protein content, and reactive oxygen/nitrogen species (RONS) protein adduction in murine skeletal muscle after 35–37 days of spaceflight. In male and female soleus muscles, spaceflight led to drastic impairments in Ca2+ uptake despite significant increases in SERCA1a protein content. We attribute this impairment to an increase in RONS production and elevated total protein tyrosine (T) nitration and cysteine (S) nitrosylation. Contrarily, in the tibialis anterior (TA), we observed an enhancement in Ca2+ uptake, which we attribute to a shift towards a faster muscle fiber type (i.e., increased myosin heavy chain IIb and SERCA1a) without elevated total protein T-nitration and S-nitrosylation. Thus, spaceflight affects SERCA function differently between the soleus and TA.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Characterizing SERCA Function in Murine Skeletal Muscles after 35–37 Days of Spaceflight

Braun

Geromella

Hamstra

et al. 2021

IJMS

View full text Add to dashboard Cite

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“…17,31 Indeed, the clinical improvement after IVIG was successful in all the patients, although one of them showed only a partial rapid recovery of weakness which might be explained by the prolonged bed rest and intubation. [32][33][34] In addition to the already recognized use of anti-IL-6…”

Section: Discussionmentioning

confidence: 99%

Cerebrospinal fluid and serum interleukins 6 and 8 during the acute and recovery phase in COVID‐19 neuropathy patients

Manganotti

Bellavita

Tommasini

et al. 2021

Journal of Medical Virology

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This case series describes three patients affected by severe acute respiratory syndrome coronavirus 2, who developed polyradiculoneuritis as a probable neurological complication of coronavirus disease 2019 (COVID‐19). A diagnosis of Guillain Barré syndrome was made on the basis of clinical symptoms, cerebrospinal fluid analysis, and electroneurography. In all of them, the therapeutic approach included the administration of intravenous immunoglobulin (0.4 gr/kg for 5 days), which resulted in the improvement of neurological symptoms. Clinical neurophysiology revealed the presence of conduction block, absence of F waves, and in two cases, a significant decrease in amplitude of compound motor action potential cMAP. Due to the potential role of inflammation on symptoms development and prognosis, interleukin‐6 (IL‐6) and IL−8 levels were measured in serum and cerebrospinal fluid during the acute phase, while only serum was tested after recovery. Both IL‐6 and IL‐8 were found increased during the acute phase, both in the serum and cerebrospinal fluid, whereas 4 months after admission (at complete recovery), only IL‐8 remained elevated in the serum. These results confirm the inflammatory response that might be linked to peripheral nervous system complications and encourage the use of IL‐6 and IL‐8 as prognostic biomarkers in COVID‐19.

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“…Interestingly, the severe unloading-induced decrement in maximal force production was roughly the same whether muscle contraction was elicited by stimulating nerve terminal endings, or the sarcolemma. This made it difficult initially to attribute loss of strength specifically to either neural or myofiber impairment; both have been shown to negatively impact contractile force ( Deschenes et al, 2017 ; Monti et al, 2021 ; Padilla et al, 2021 ). With little doubt, the difference in loss of peak force following unloading cannot be explained by differential adaptations in muscle size as results showed that adult and juvenile muscles experienced similar atrophy with unloading.…”

Section: Discussionmentioning

confidence: 99%

“…This is important because disturbances in synaptic activity of the NMJ disrupts normal function of skeletal muscle and its capacity to perform the necessities, and rigors of daily living ( Metter et al, 2002 ; Newman et al, 2006 ; Hairi et al, 2010 ). And while subtotal disuse of the neuromuscular system, i.e., unloading, immobilization, bed rest, has clearly been shown to disrupt neuromuscular function in adults ( Booth and Gollnick, 1983 ; Hackney and Ploutz-Snyder, 2012 ; Monti et al, 2021 ), little is known about how rapidly growing, maturing neuromuscular systems react to the imposition of disuse. Thus, the objective of the present investigation was to compare the deleterious effects of disuse in the form of muscle unloading on mature, fully developed vs. juvenile, rapidly developing neuromuscular systems characterized by accelerated plasticity.…”

Section: Introductionmentioning

confidence: 99%

Juvenile Neuromuscular Systems Show Amplified Disturbance to Muscle Unloading

et al. 2021

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Muscle unloading results in severe disturbance in neuromuscular function. During juvenile stages of natural development, the neuromuscular system experiences a high degree of plasticity in function and structure. This study aimed to determine whether muscle unloading imposed during juvenile development would elicit more severe disruption in neuromuscular function than when imposed on fully developed, mature neuromuscular systems. Twenty juvenile (3 months old) and 20 mature (8 months old) rats were equally divided into unloaded and control groups yielding a total of four groups (N = 10/each). Following the 2 week intervention period, soleus muscles were surgically extracted and using an ex vivo muscle stimulation and recording system, were examined for neuromuscular function. The unloading protocol was found to have elicited significant (P ≤ 0.05) declines in whole muscle wet weight in both juvenile and mature muscles, but of a similar degree (P = 0.286). Results also showed that juvenile muscles displayed significantly greater decay in peak force due to unloading than mature muscles, such a finding was also made for specific tension or force/muscle mass. When examining neuromuscular efficiency, i.e., function of the neuromuscular junction, it again was noted that juvenile systems were more negatively affected by muscle unloading than mature systems. These results indicate that juvenile neuromuscular systems are more sensitive to the effects of unloading than mature ones, and that the primary locus of this developmental related difference is likely the neuromuscular junction as indicated by age-related differences in neuromuscular transmission efficiency.

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Neuromuscular junction instability and altered intracellular calcium handling as early determinants of force loss during unloading in humans

Cited by 63 publications

References 113 publications

Characterizing SERCA Function in Murine Skeletal Muscles after 35–37 Days of Spaceflight

Characterizing SERCA Function in Murine Skeletal Muscles after 35–37 Days of Spaceflight

Cerebrospinal fluid and serum interleukins 6 and 8 during the acute and recovery phase in COVID‐19 neuropathy patients

Juvenile Neuromuscular Systems Show Amplified Disturbance to Muscle Unloading

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