TY - JOUR
T1 - Human skeletal muscle mitochondrial dynamics in relation to oxidative capacity and insulin sensitivity
AU - Houzelle, Alexandre
AU - Jorgensen, Johanna A.
AU - Schaart, Gert
AU - Daemen, Sabine
AU - van Polanen, Nynke
AU - Fealy, Ciaran E.
AU - Hesselink, Matthijs K. C.
AU - Schrauwen, Patrick
AU - Hoeks, Joris
N1 - Funding Information:
The work of JH is supported by a Vidi (Grant 917.14.358) for innovative research from the Netherlands Organization for Scientific Research (NWO) and a Senior Fellowship from the Dutch Diabetes Research Foundation (grant number 2013.82.1639).
Publisher Copyright:
© 2020, The Author(s).
PY - 2021/2
Y1 - 2021/2
N2 - Aims/hypothesis Mitochondria operate in networks, adapting to external stresses and changes in cellular metabolic demand and are subject to various quality control mechanisms. On the basis of these traits, we here hypothesise that the regulation of mitochondrial networks in skeletal muscle is hampered in humans with compromised oxidative capacity and insulin sensitivity.Methods In a cross-sectional design, we compared four groups of participants (selected from previous studies) ranging in aerobic capacity and insulin sensitivity, i.e. participants with type 2 diabetes (n = 11), obese participants without diabetes (n = 12), lean individuals (n = 10) and endurance-trained athletes (n = 12); basal, overnight fasted muscle biopsies were newly analysed for the current study and we compared the levels of essential mitochondrial dynamics and quality control regulatory proteins in skeletal muscle tissue.Results Type 2 diabetes patients and obese participants were older than lean participants and athletes (58.6 +/- 4.0 and 56.7 +/- 7.2 vs 21.8 +/- 2.5 and 25.1 +/- 4.3 years, p <0.001, respectively) and displayed a higher BMI (32.4 +/- 3.7 and 31.0 +/- 3.7 vs 22.1 +/- 1.8 and 21.0 +/- 1.5 kg/m(2), p <0.001, respectively) than lean individuals and endurance-trained athletes. Fission protein 1 (FIS1) and optic atrophy protein 1 (OPA1) protein content was highest in muscle from athletes and lowest in participants with type 2 diabetes and obesity, respectively (FIS1: 1.86 +/- 0.79 vs 0.79 +/- 0.51 AU, p = 0.002; and OPA1: 1.55 +/- 0.64 vs 0.76 +/- 0.52 AU, p = 0.014), which coincided with mitochondrial network fragmentation in individuals with type 2 diabetes, as assessed by confocal microscopy in a subset of type 2 diabetes patients vs endurance-trained athletes (n = 6). Furthermore, lean individuals and athletes displayed a mitonuclear protein balance that was different from obese participants and those with type 2 diabetes. Mitonuclear protein balance also associated with heat shock protein 60 (HSP60) protein levels, which were higher in athletes when compared with participants with obesity (p = 0.048) and type 2 diabetes (p = 0.002), indicative for activation of the mitochondrial unfolded protein response. Finally, OPA1, FIS1 and HSP60 correlated positively with aerobic capacity (r = 0.48, p = 0.0001; r = 0.55, p <0.001 and r = 0.61, p <0.0001, respectively) and insulin sensitivity (r = 0.40, p = 0.008; r = 0.44, p = 0.003 and r = 0.48, p = 0.001, respectively).Conclusions/interpretation Collectively, our data suggest that mitochondrial dynamics and quality control in skeletal muscle are linked to oxidative capacity in humans, which may play a role in the maintenance of muscle insulin sensitivity.
AB - Aims/hypothesis Mitochondria operate in networks, adapting to external stresses and changes in cellular metabolic demand and are subject to various quality control mechanisms. On the basis of these traits, we here hypothesise that the regulation of mitochondrial networks in skeletal muscle is hampered in humans with compromised oxidative capacity and insulin sensitivity.Methods In a cross-sectional design, we compared four groups of participants (selected from previous studies) ranging in aerobic capacity and insulin sensitivity, i.e. participants with type 2 diabetes (n = 11), obese participants without diabetes (n = 12), lean individuals (n = 10) and endurance-trained athletes (n = 12); basal, overnight fasted muscle biopsies were newly analysed for the current study and we compared the levels of essential mitochondrial dynamics and quality control regulatory proteins in skeletal muscle tissue.Results Type 2 diabetes patients and obese participants were older than lean participants and athletes (58.6 +/- 4.0 and 56.7 +/- 7.2 vs 21.8 +/- 2.5 and 25.1 +/- 4.3 years, p <0.001, respectively) and displayed a higher BMI (32.4 +/- 3.7 and 31.0 +/- 3.7 vs 22.1 +/- 1.8 and 21.0 +/- 1.5 kg/m(2), p <0.001, respectively) than lean individuals and endurance-trained athletes. Fission protein 1 (FIS1) and optic atrophy protein 1 (OPA1) protein content was highest in muscle from athletes and lowest in participants with type 2 diabetes and obesity, respectively (FIS1: 1.86 +/- 0.79 vs 0.79 +/- 0.51 AU, p = 0.002; and OPA1: 1.55 +/- 0.64 vs 0.76 +/- 0.52 AU, p = 0.014), which coincided with mitochondrial network fragmentation in individuals with type 2 diabetes, as assessed by confocal microscopy in a subset of type 2 diabetes patients vs endurance-trained athletes (n = 6). Furthermore, lean individuals and athletes displayed a mitonuclear protein balance that was different from obese participants and those with type 2 diabetes. Mitonuclear protein balance also associated with heat shock protein 60 (HSP60) protein levels, which were higher in athletes when compared with participants with obesity (p = 0.048) and type 2 diabetes (p = 0.002), indicative for activation of the mitochondrial unfolded protein response. Finally, OPA1, FIS1 and HSP60 correlated positively with aerobic capacity (r = 0.48, p = 0.0001; r = 0.55, p <0.001 and r = 0.61, p <0.0001, respectively) and insulin sensitivity (r = 0.40, p = 0.008; r = 0.44, p = 0.003 and r = 0.48, p = 0.001, respectively).Conclusions/interpretation Collectively, our data suggest that mitochondrial dynamics and quality control in skeletal muscle are linked to oxidative capacity in humans, which may play a role in the maintenance of muscle insulin sensitivity.
KW - Fission
KW - FIS1
KW - Fusion
KW - HSP60
KW - Insulin sensitivity
KW - Mitochondria
KW - OPA1
KW - Oxidative phosphorylation
KW - Skeletal muscle
KW - UNFOLDED PROTEIN RESPONSE
KW - RESISTANCE
KW - DYSFUNCTION
KW - ACTIVATION
KW - LONGEVITY
KW - NETWORK
KW - PATHWAY
KW - HEALTH
U2 - 10.1007/s00125-020-05335-w
DO - 10.1007/s00125-020-05335-w
M3 - Article
C2 - 33258025
SN - 0012-186X
VL - 64
SP - 424
EP - 436
JO - Diabetologia
JF - Diabetologia
IS - 2
ER -