title: Heart failure with preserved ejection fraction induces molecular, mitochondrial, histological, and functional alterations in rat respiratory and limb skeletal muscle.
abstract: OBJECTIVE
  Peripheral muscle dysfunction is a key mechanism contributing to exercise intolerance (i.e. breathlessness and fatigue) in heart failure patients with preserved ejection fraction (HFpEF); however, the underlying molecular and cellular mechanisms remain unknown. We therefore used an animal model to elucidate potential molecular, mitochondrial, histological, and functional alterations induced by HFpEF in the diaphragm and soleus, while also determining the possible benefits associated with exercise training.
  
  
  RESULTS
  Female Dahl salt-sensitive rats were fed a low (CON; n = 10) or high salt (HFpEF; n = 11) diet of 0.3% or 8% NaCl, respectively, or a high salt diet in combination with treadmill exercise training (n = 11). Compared with low-salt rats, high-salt rats developed (P < 0.05) HFpEF. Compared with CON, the diaphragm of HFpEF rats demonstrated (P < 0.05): a fibre type shift from fast-to-slow twitch; fibre atrophy; a decreased pro-oxidative but increased anti-oxidant capacity; reduced proteasome activation; impaired in situ mitochondrial respiration; and in vitro muscle weakness and increased fatigability. The soleus also demonstrated numerous alterations (P < 0.05), including fibre atrophy, decreased anti-oxidant capacity, reduced mitochondrial density, and increased fatigability. Exercise training, however, prevented mitochondrial and functional impairments in both the diaphragm and soleus (P < 0.05).
  
  
  CONCLUSIONS
  Our findings are the first to demonstrate that HFpEF induces significant molecular, mitochondrial, histological, and functional alterations in the diaphragm and soleus, which were attenuated by exercise training. These data therefore reveal novel mechanisms and potential therapeutic treatments of exercise intolerance in HFpEF.
authors: Department of Internal Medicine and Cardiology, Leipzig University-Heart Centre, Strümpellstrasse 39, D-04289, Leipzig, Germany.
authors: T Scott
authors: TS
authors: Bowen
authors: Natale P L
authors: NP
authors: Rolim
authors: Tina
authors: T
authors: Fischer
authors: Fredrik H
authors: FH
authors: Baekkerud
authors: Alessandra
authors: A
authors: Medeiros
authors: Sarah
authors: S
authors: Werner
authors: Eivind
authors: E
authors: Brønstad
authors: Oivind
authors: O
authors: Rognmo
authors: Norman
authors: N
authors: Mangner
authors: Axel
authors: A
authors: Linke
authors: Gerhard
authors: G
authors: Schuler
authors: Gustavo J J
authors: GJ
authors: Silva
authors: Ulrik
authors: U
authors: Wisløff
authors: Volker
authors: V
authors: Adams
mesh_terms: D000818:Animals; D002374:Catalase / Q000378:metabolism; D003964:Diaphragm / Q000378:metabolism / Q000503:physiopathology*; D017079:Exercise Tolerance / Q000502:physiology; D005260:Female; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology*; D008931:Mitochondria, Muscle / Q000378:metabolism*; D023421:Models, Animal; D018482:Muscle, Skeletal / Q000378:metabolism / Q000503:physiopathology*; D018994:Myosin Light Chains / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D020303:Rats, Inbred Dahl; D013318:Stroke Volume / Q000502:physiology*; D013482:Superoxide Dismutase / Q000378:metabolism; D019209:Troponin C / Q000378:metabolism
chemical_list: D018994:Myosin Light Chains; D019209:Troponin C; D002374:Catalase; D013482:Superoxide Dismutase; D019255:NADPH Oxidases
keywords: Diaphragm; Diastolic dysfunction; Exercise training; Mitochondrial respiration; Soleus