Živčnomišična oslabitev in transkriptomski profil sarkopenične mišice pri ljudeh

Sarkopenija je stanje, pri katerem je opazna "zmanjšana mišična moč, nizka količina/kakovost mišic in poslabšana telesna zmogljivost". Gre za eno izmed zdravstvenih stanj, s katerimi se soočajo starejši odrasli, in je priznana kot bolezen, povezana s starostjo in/ali pridruženimi boleznimi. Sarkopenija močno vpliva na izgubo samostojnosti, invalidnost, potrebo po dolgotrajni oskrbi ter celo na umrljivost. Glede na njen vpliv na življenje starejših odraslih, saj omejuje njihovo sposobnost skrbeti zase in sodelovati v družbenem življenju, je študija, v kateri nameravajo raziskati molekularne vzroke nevrogenega prispevka k sarkopeniji, izjemno pomembna.

Študija prvič obravnava vprašanje bioloških sprememb, ki vplivajo na obseg nevromišičnih okvar pri sarkopeniji. Z molekularnimi analizami in elektrofiziološkimi meritvami bodo preučili funkcionalno celovitost nevromišičnega stika z namenom ugotovitve dejavnikov, ki vodijo v nefunkcionalnost mišic. Za boljše razumevanje teh sprememb bodo uporabili enocelično RNA-sekvenciranje (scRNA-seq), ki omogoča pridobivanje informacij o transkriptomski mreži genov, ki vplivajo na delovanje mišic, na ravni posameznih celic. Glede na trenutno pomanjkanje informacij o transkriptomskem profilu posameznih celic v skeletnih mišicah je to ambiciozno delo ključno za boljše razumevanje celične dinamike, notranjih dejavnikov ter novih označevalcev, povezanih z mišicami in njihovim okoljem v patofizioloških razmerah. Z molekularnim razumevanjem tega stanja ter zmožnostjo moduliranja celične disfunkcije se bo v prihodnjih desetletjih odprlo novo okno za farmakološke pristope z uporabo mRNA/miRNA tehnologije.

Projekt je financiran na podlagi pogodbe o izvedbi in (so)financiranju raziskovalnega projekta za »krepitev mednarodne mobilnosti slovenskih raziskovalcev in raziskovalnih organizacij ter spodbujanje mednarodnega vključevanja slovenskih prijaviteljev« (šifra akcije C3.K8.IC) v okviru Načrta za okrevanje in odpornost.

Sarcopenia, nowadays defined as "low muscle strength, low muscle quantity/quality, and low physical performance," is one of the health conditions faced byolder adults, and it is recognised as an age-related disease. It is a major contributor to loss of independence, disability, need for long-term care, as well asmortality. Given the impact that sarcopenia has on the lives of older adults, limiting their ability to care for themselves and participate in social life, the study aims to carefully investigate the molecular causes of the neurogenic contribution to sarcopenia, which could lead to the development of new treatmentstrategies.

This study for the first time address the question of biological changes affecting NMJ instability and impaired MU remodeling in sarcopenic muscle. Through molecular analysis and electrophysiological measurements, we will examine functional integrity of the neuromuscular junction to study a larger number ofindividuals and determine a specific biomarker concentration and thresholds of electrophysiological measurements at which these changes occur, as well as theextent of neuromuscular impairment in sarcopenia.

To better understand these changes, we will apply snRNA-seq to sarcopenia-related profiling to identify novel nuclear heterogeneity and transcriptionaldiversity specific to humans.

The proposed snRNA-seq may provide more information about the sarcopenic network of genes that affect muscle function. With molecular understanding ofthis condition and the ability to modulate cellular dysfunction, a new window for pharmacological approaches will open in the coming decades with mRNA/miRNA technologies on rise. Considering the current lack of information of transcriptional profile in aged skeletal muscle, this work is ambitious and crucial for a better understanding of cellular dynamics, intrinsic factors, and novel signatures associated with myofibers and their environment underpathophysiological conditions.

The project is funded under the contract for the implementation and (co-)financing of the research project "Strengthening the international mobility of Slovenian researchers and research organisations and promoting the international involvement of Slovenian applicants" (Action code C3.K8.IC) under the Economic Recovery and Resilience Plan.